The present invention relates to a substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof having excellent insulin resistance improving action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, peroxisome proliferator activated receptor (which will hereinafter be abbreviated as xe2x80x9cPPARxe2x80x9d) activating action, anti-osteoporosis action, leukotrienes antagonism, fat-cell formation promoting action, cancer-cell proliferation inhibitory action and calcium antagonism; a pharmaceutical composition comprising, as an effective ingredient, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof; use of the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical composition; a method for the prevention or treatment of diabetes or like diseases, which comprises administering an effective amount of the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof to a warm-blooded animal; or a pharmaceutical composition obtained by using, in combination, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof and at least one compound selected from xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
It is reported that thiazolidine compounds, oxazolidine compounds and the like are useful as preventive agents and/or remedies for various diseases such as diabetes and hyperlipidemia.
For example, a number of thiazolidine compounds having hypoglycemic action are disclosed in Chem. Pharm. Bull., 30, 3580-3600(1982), Prog. Clin. Biol. Res., 265, 177-192(1988), Diabetes, 37(11), 1549-1558(1988), Arzneim.-Forsch., 40(1), 37-42(1990), EP0441605A and the like.
The action of thiazolidine compounds on hyperlipidemia is reported in Diabetes, 40(12), 1669-1674(1991), Am. J. Physiol., 267(1 Pt 1), E95-E101(1994), Diabetes, 43(10), 1203-1210(1994) and the like.
The action of thiazolidine compounds on glucose tolerance insufficiency and insulin resistance is disclosed in Arzneim.-Forsch., 40(2 Pt 1), 156-162(1990), Metabolism, 40(10), 1025-1230(1991), Diabetes, 43(2), 204-211(1994) and the like.
It is recently reported in N. Engl. J. Med., 331(18), 1226-1227(1994) that a normal person having insulin resistance has developed diabetes without glucose tolerance insufficiency and also that a medicament for improving insulin resistance is useful as a preventive agent the onset of diabetes in such a normal person.
The action of thiazolidine compounds on hypertension is reported in Metabolism, 42(1), 75-80(1993), Am. J. Physiol., 265(4 Pt 2), R726-R732(1933), Diabetes, 43(2), 204-211(1994) and the like.
The action of thiazolidine compounds on coronary artery diseases is reported in Am. J. Physiol., 265(4 Pt 2), R726-R732(1933), Hypertension, 24(2), 170-175(1994) and the like.
The action of thiazolidine compounds on arteriosclerosis is reported in Am. J. Physiol., 265(4 Pt 2), R726-R732(1933) and the like.
The action of thiazolidine compounds on cachexia is reported in Endocrinology, 135(5), 2279-2282(1994), Endocrinology, 136(4), 1474-1481(1995) and the like.
Among thiazolidine compounds having hypoglycemic action, compounds containing a heterocyclic group are disclosed in WO92/07839A, WO92/07850A and EP00745600A.
In addition, oxazolidine-2,4-dione compounds having hypoglycemic action are disclosed in WO92/02520A and the like.
In WO92/03425A, it is disclosed that compounds containing a 3,5-dioxooxadiazolidin-2-ylmethylphenyl or a N-hydroxyureido group exhibit hypoglycemic action.
In EP00676398A, 5-{4-[5-(3,5-di-t-butyl-4-hydroxyphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy]benzyl}thiazolidine-2,4-dione is disclosed only as one of the exemplified compounds.
As a result of investigation for many years on the synthesis of a series of substituted fused heterocyclic compounds and their pharmacological activity, the present inventors have found that a substituted condensed heterocyclic compound having a novel structure has excellent insulin-resistance improving action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid-peroxide-production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotrienes antagonism, fat-cell-formation promoting action, cancer-cell proliferation inhibitory action and calcium antagonism; has reduced side effects; and moreover has high fat solubility.
Another object of the present invention is to provide a preventive agent and/or remedy, which comprises as an effective ingredient the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof, for diseases alleviated by the above-described actions such as diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g. brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts.
Another object of the present invention is to provide a pharmaceutical composition (particularly suited is a preventive agent and/or remedy for diabetes or diabetic complications) obtained by using, in combination, the above-described substituted fused heterocyclic compound or a pharmacologically acceptable salt thereof and at least one compound selected from xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
The present invention thus provides (i) pharmaceutical compositions containing as an active ingredient, a substituted fused heterocyclic compound of the formula (I) or a pharmacologically acceptable salt or prodrug thereof and (ii) methods of treating by administering said active ingredient to a warm-blooded animal, particularly to a human.
In the present invention, a substituted fused heterocyclic compound is represented by the following formula (I): 
wherein:
R1 represents a group of the following formula: 
xe2x80x83or a group of the following formula: 
xe2x80x83[in which:
R4 represents a phenyl group which is substituted with 1 to 5 substituents selected from Substituents xcex1 or a pyridyl group which may be substituted with 1 to 4 substituents selected from Substituents xcex1,
R5 represents a hydrogen atom or a substituent selected from Substituents xcex1
R6 represents a hydrogen atom, a C1-6 alkyl group, a C6-10 aryl group which may be substituted with 1 to 3 substituents selected from Substituents xcex2 or a C7-16 aralkyl group which may be substituted with 1 to 3 substituents selected from Substituents xcex2,
D represents an oxygen or sulfur atom, and
E represents a CH group or nitrogen atom],
R2 represents a hydrogen atom or a substituent selected from Substituents xcex1,
R3 represents a group of the following formula: 
A represents a C1-6 alkylene group, and
B represents an oxygen or sulfur atom,
with the proviso that 5-{4-[5-(3,5-di-t-butyl-4-hydroxyphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy]benzyl}thiazolidine-2,4-dione is excluded.
 less than Substituents xcex1 greater than 
A halogen atom, a hydroxyl group, a C1-6 alkyl group, a halogeno(C1-6 alkyl) group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group which may be substituted with substituents selected from Substituents xcex3, C3-10 cycloalkyl, C6-10 aryl, C7-16 aralkyl, C6-10 aryloxy, C7-16 aralkyloxy and C6-10 arylthio groups which may each be substituted with 1 to 3 substituents selected from Substituents xcex2, a C1-7 aliphatic acyloxy group, a 4- to 7-membered saturated nitrogen-containing heterocyclic group, a 5- or 6-membered aromatic nitrogen-containing heterocyclic group, a nitro group, and a cyano group.
 less than Substituents xcex2 greater than 
A halogen atom, a hydroxyl group, a C1-6 alkyl group, a halogeno(C1-6 alkyl) group, a C1-6 alkoxy group, an amino group which may be substituted with substituents selected from Substituents xcex3, a C6-10 aryl group and a nitro group.
 less than Substituents xcex3 greater than 
A C1-10 alkyl group, and C6-10 aryl and C7-16 aralkyl groups each of which may have a substituent and an acyl group which may have substituents (said acyl group is a C1-7 aliphatic acyl group or a C7-11 aromatic acyl, C8-12 aromatic aliphatic acyl, C4-11 cycloalkylcarbonyl or 5- or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group each of which may have substituents).
In the above description, examples of the xe2x80x9chalogen atomxe2x80x9d in the definition of Substituents xcex1 and xcex2 include fluorine, chlorine, bromine and iodine atoms, of which fluorine and chlorine atoms are preferred.
In the above description, the xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of R6 and Substituents xcex1, xcex2 and xcex3 is a linear or branched C1-6 alkyl group. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methypentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups. With reference to R6, a C1-4 alkyl group is preferred, of which a C1-2 alkyl group is more preferred and a methyl group is particularly preferred. With reference to Substituents xcex1, methyl and t-butyl groups are preferred, while with reference to Substituents xcex2, methyl, ethyl and t-butyl groups are preferred.
In the above description, the xe2x80x9chalogeno(C1-6 alkyl) groupxe2x80x9d in the definition of Substituents xcex1 or xcex2 is the above-exemplified C1-6 alkyl group having one to three of the above-exemplified halogen atoms bound thereto. Examples include trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and 2,2-dibromoethyl groups, of which a halogeno(C1-2 alkyl) group is preferred and a trifluoromethyl group is particularly preferred.
In the above description, the xe2x80x9cC1-6 alkoxy groupxe2x80x9d in the definition of Substituents xcex1 and xcex2 is the above-described C1-6 alkyl group bound to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and 2-ethylbutoxy groups, of which a C1-2 alkoxy group is preferred and a methoxy group is particularly preferred.
In the above description, the xe2x80x9cC1-6 alkylthio groupxe2x80x9d in the definition of Substituents xcex1 is the above-exemplified C1-6 alkyl group bound to a sulfur atom. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio groups, of which a C1-2 alkylthio group is preferred and a methylthio group is particularly preferred.
In the above description, the xe2x80x9camino group which may be substituted with substituents selected from Substituents xcex3xe2x80x9d in the definition of each of Substituents xcex1 and xcex2 means an amino group which may be substituted with 1 or 2 substituents which are the same or different and are selected from Substituents xcex3 consisting of C1-10 alkyl groups, C6-10 aryl and C7-16 aralkyl groups each of which may have substituents (said substituents means 1 to 3 groups selected from the group consisting of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy and C1-6 alkylthio groups) and acyl groups which may have substituents (each of which means a C1-7 aliphatic acyl group or a C7-11 aromatic acyl, C8-12 aromatic-aliphatic acyl, C4-11 cycloalkylcarbonyl or 5- or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy and C1-6 alkylthio groups).
In the above description, the xe2x80x9cC1-10 alkyl groupxe2x80x9d in the definition of Substituents xcex3 means a linear or branched alkyl group having 1 to 10 carbon atoms and examples include the above-exemplified C1-6 alkyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl groups, of which C1-8 alkyl groups are preferred and methyl, butyl, isobutyl, pentyl, hexyl, heptyl and octyl groups are particularly preferred.
In the above description, the C6-10 aryl part of the xe2x80x9cC6-10 aryl group which may have a substituentxe2x80x9d in the definition of Substituents xcex3 means a C6-10 aromatic hydrocarbon group and examples include phenyl, indenyl and naphthyl groups, of which phenyl groups are preferred.
In the above description, the C7-16 aralkyl part of the xe2x80x9cC7-16 aralkyl group which may have a substituentxe2x80x9d in the definition of Substituents xcex3 means the above-described C6-10 aryl group bound to the above-described C1-6 alkyl group and examples include benzyl, naphthylmethyl, indenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphtylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and 6-naphthylhexyl groups, of which benzyl groups are preferred.
In the above description, the xe2x80x9cC1-7 aliphatic acyl groupxe2x80x9d in the definition of Substituents xcex3 means a hydrogen atom or a saturated or unsaturated C1-6 chain hydrocarbon group bound to a carbonyl group and examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl and crotonoyl groups, of which acetyl, propionyl and pivaloyl groups are preferred and acetyl groups are particularly preferred.
In the above description, the C7-11 aromatic acyl part of the xe2x80x9cC7-11 aromatic acyl group which may have substituentsxe2x80x9d in the definition of Substituents xcex3 means a C6-10 aryl group bound to a carbonyl group and examples include benzoyl, 1-indanecarbonyl, 2-indanecarbonyl and 1- or 2-naphthoyl groups, of which benzoyl and naphthoyl groups are preferred.
In the above description, the C8-12 aromatic-aliphatic acyl part of the xe2x80x9cC8-12 aromatic-aliphatic acyl group which may have substituentsxe2x80x9d in the definition of Substituents xcex3 means a phenyl group bound to a C2-6 aliphatic acyl group and examples include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl and 6-phenylhexanoyl groups, of which the phenylacetyl group is preferred.
In the above description, the C4-11 cycloalkylcarbonyl part of the xe2x80x9cC4-11 cycloalkylcarbonyl group which may have substituentsxe2x80x9d in the definition of Substituents xcex3 means a C3-10 cycloalkyl group (which means a 3- to 10-membered saturated cyclic hydrocarbon group which may be condensed and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl groups, of which C3-6 cycloalkyl groups are preferred) bound to a carbonyl group and examples include cyclopropanoyl, cyclobutyryl, cyclopentanoyl, cyclohexanoyl, cycloheptylcarbonyl, norbornylcarbonyl and adamantylcarbonyl groups, of which C4-7 cycloalkylcarbonyl groups are preferred and cyclopentanoyl and cyclohexanoyl groups are particularly preferred.
In the above description, the xe2x80x9c5- or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group part of the 5- or 6-membered aromatic nitrogen-containing heterocyclic carbonyl group which may have substituentsxe2x80x9d in the definition of Substituents xcex3 means a 5- or 6-membered aromatic heterocycle which contains at least one nitrogen atom and at the same time, may contain further hetero atoms selected from the hetero atom group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (examples of such heterocycles include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl and thiadiazolyl groups) bound to a carbonyl group and examples include pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, tetrazolylcarbonyl, nicotinoyl, isonicotinoyl, pyrazinylcarbonyl, pyrimidinylcarbonyl, pyridazinylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, oxadiazolylcarbonyl and thiadiazolylcarbonyl groups, of which pyridylcarbonyl groups are preferred and nicotinoyl and isonicotinoyl groups are particularly preferred.
Examples of the xe2x80x9camino group which may be substituted with substituents selected from Substituents xcex3xe2x80x9d in the definition of such Substituents xcex1 or xcex2 include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, phenylamino, 2-, 3- or 4-fluorophenylamino, 2-, 3- or 4-chlorophenylamino, 2-, 3- or 4-bromophenylamino, 2,3-difluorophenylamino, 2,4-difluorophenylamino, 2,4-dichlorophenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, diphenylamino, benzylamino, 2-, 3- or 4-fluorobenzylamino, 2-, 3- or 4-chlorobenzylamino, 2-, 3- or 4-bromobenzylamino, 2,3-difluorobenzylamino, 2,4-difluorobenzylamino, 2,4-dichlorobenzylamino, 1- or 2-naphthylmethylamino, 1-indenylmethylamino, 1- or 2-phenethylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino, formylamino, acetylamino, propionylamino, buturylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino, benzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, 2-, 3- or 4-fluorobenzoylamino, 2-, 3, or 4-chlorobenzoylamino, 2-, 3- or 4-bromobenzoylamino, 2,3-difluorobenzoylamino, 2,4-difluorobenzoylamino, 2,4-dichlorobenzoylamino, 2,6-diisopropylbenzoylamino, 4-trifluoromethylbenzoylamino, 4-hydroxy-3,5-dimethylbenzoylamino, 4-hydroxy-3,5-di-t-butylbenzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, 2-, 3- or 4-fluorophenylacetylamino, 2-, 3- or 4-chlorophenylacetylamino, 2-, 3- or 4-bromophenylacetylamino, 2,3-difluorophenylacetylamino, 2,4-difluorophenylacetylamino, 2,4-dichlorophenylacetylamino, cyclopropionylamino, cyclobutyrylamino, cyclopentanoylamino, cyclohexanoylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-4-trifluoromethylbenzyl-N-2,4-difluorobenzoylamino, N-2,4-difluorobenzyl-N-nicotinoylamino, N-3-chlorobenzoyl-N-methylamino, N-3-chlorobenzoyl-N-hexylamino, N-3-chlorobenzyl-N-acetylamino, N-2,4-difluorobenzoyl-N-hexylamino, N-2,4-difluorobenzoyl-N-phenylamino, N-2,4-difluorobenzoyl-N-phenylamino, N-4-trifluoromethylbenzoyl-N-butylamino, N-3,5-di-t-butyl-4-hydroxybenzoyl-N-hexylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanoylamino, N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino and N-isonicotinoyl-N-hexylamino groups, of which amino groups, amino groups substituted with one or two substituents (said substituents may be the same or different and each independently represents a group selected from the class consisting of C1-10 alkyl groups and C6-10 aryl and C7-16 aralkyl groups which may each have substituents) and acylamino groups which may be substituted with a substituent selected from Substituents xcex3 (the acylamino group means an amino group substituted with the above-described acyl group) are preferred; amino groups, mono- or di-C1-10 alkylamino groups and acylamino groups which may each be substituted with a C1-10 alkyl group or a C7-16 aralkyl group which may have a substituent are more preferred; amino, mono- or di-C1-10 aralkylamino groups or C7-11 aromatic acylamino, C4-11 cycloalkylcarbonylamino and 5- or 6-membered aromatic nitrogen-containing heterocyclic carbonylamino groups which may each have a substituent are still more preferred; and amino, dimethylamino, hexylamino, acetylamino, benzoylamino, 3-chlorobenzoylamino, 2,4-difluorobenzoylamino, 4-hydroxy-3,5-di-t-butylbenzoylamino, naphthoylamino, cyclopentanoylamino, cyclohexanoylamino, nicotinoylamino, isonicotinoylamino, N-acetyl-N-hexylamino and adamantylcarbonylamino groups are particularly preferred.
The C3-10 cycloalkyl part of the xe2x80x9cC3-10 cycloalkyl group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d has the same meaning as described above. Preferred examples include C3-10 cycloalkyl groups which may each be substituted with one substituent selected from Substituents xcex2, of which C3-10 cycloalkyl groups which may each be substituted with one substituent selected from the group consisting of halogen atoms and C1-6 alkyl and halogeno(C1-6 alkyl) groups; adamantyl groups which may be substituted with one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, t-butyl group, trifluoromethyl group, methoxy group, amino group, methylamino group or dimethylamino group is more preferred; and an adamantyl group is particularly preferred.
In the above description, the C6-10 aryl part of the xe2x80x9cC6-10 aryl groupxe2x80x9d of the xe2x80x9cC6-10 aryl group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d in the definitions of R6 and Substituents xcex1, and that of the xe2x80x9cC6-10 aryl groupxe2x80x9d or in the definition of Substituents xcex2 has the same meaning as described above. As R6, preferred are phenyl groups which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6 alkyl and halogeno(C1-6 alkyl) groups and particularly preferred are phenyl groups which may each be substituted with one substituent selected from the group consisting of fluorine and chlorine atoms, and hydroxyl, methyl, ethyl and trifluoromethyl groups. With reference to Substituents xcex1, preferred are C6-10 aryl groups which may each be substituted with one substituent selected from Substituents xcex2; more preferred are C6-10 aryl groups which may each be substituted with one amino group which may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkyl group, a halogeno(C1-6 alkyl) group, a C1-6 alkoxy group or a substituent selected from Substituents xcex3; still more preferred are phenyl groups which may be substituted with one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, t-butyl group, trifluoromethyl group, methoxy group, amino group, methylamino group or dimethylamino group; and particularly preferred is a phenyl or 4-hydroxyphenyl group. With reference to Substituents xcex2, preferred is a phenyl group.
In the above description, the C7-16 aralkyl part of the xe2x80x9cC7-16 aralkyl group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d in the definition of R6 or Substituents xcex1 has the same meaning as described above. With reference to R6, preferred are benzyl groups which may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms and hydroxyl, C1-6 alkyl and halogeno(C1-6 alkyl) groups and particularly preferred are benzyl groups which may be substituted with a substituent selected from the group consisting of fluorine and chlorine atoms and hydroxyl, methyl, ethyl and trifluoromethyl groups. In reference to Substituent xcex1, preferred are C7-16 aralkyl groups which may each be substituted with one substituent selected from Substituents xcex2; more preferred are benzyl groups which may be substituted with an amino group which may be substituted with a substituent selected from a halogen atom, hydroxyl group, C1-6 alkyl group, halogeno(C1-6 alkyl) group, C1-6 alkoxy group and Substituents xcex3; still more preferred are benzyl groups which may be substituted with one fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, t-butyl group, trifluoromethyl group, methoxy group, amino group, methylamino group or dimethylamino group; and particularly preferred are benzyl groups.
In the above description, the C6-10 aryloxy part of the xe2x80x9cC6-10 aryloxy group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d means the above-described C6-10 aryl group bound to an oxygen atom and examples include phenoxy, 1-indenyloxy, 2-indenyloxy, 3-indenyloxy, 1-naphthyloxy and 2-naphthyloxy groups, of which phenoxy groups are preferred.
In the above description, the C7-16 aralkyloxy part of the xe2x80x9cC7-16 aralkyloxy group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d in the definition of Substituents xcex1 means the above-described C7-16 aralkyl group bound to an oxygen atom and examples include benzyloxy, naphthylmethoxy, indenylmethoxy, diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylethoxy, 2-naphthylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, 1-naphthylpropoxy, 2-naphthylpropoxy, 3-naphthylpropoxy, 1-phenylbutoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy, 1-naphthylbutoxy, 2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy, 5-phenylpentyloxy, 5-naphthylpentyloxy, 6-phenylhexyloxy and 6-naphthylhexyloxy groups, of which benzyloxy groups are preferred.
In the above description, the C6-10 arylthio part of the xe2x80x9cC6-10 arylthio group which may be substituted with 1 to 3 substituents selected from Substituents xcex2xe2x80x9d means the above-described C6-10 aryl group bound to a sulfur atom and examples include phenylthio, 1-indenylthio, 2-indenylthio, 3-indenylthio, 1-naphthylthio and 2-naphthylthio groups, of which phenylthio groups are preferred.
In the above description, the xe2x80x9cC1-7 aliphatic acyloxy groupxe2x80x9d in the definition of Substituents xcex1 is the above-exemplified C1-7 aliphatic acyl group bound to an oxygen atom. Examples include formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy and crotonoyloxy groups, of which acetoxy groups are preferred.
In the above description, the xe2x80x9c4- to 7-membered saturated nitrogen-containing heterocyclic groupxe2x80x9d in the definition of Substituents xcex1 means a 4- to 7-membered saturated heterocyclic group which contains at least one nitrogen atom and at the same time may contain further hetero atoms selected from the hetero atom group consisting of nitrogen, oxygen and sulfur atoms. Examples include azetidinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and homopiperazinyl groups, of which pyrrolidinyl, piperidinyl and morpholinyl groups are preferred and pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl groups are particularly preferred.
In the above description, the xe2x80x9c5- or 6-membered aromatic nitrogen-containing heterocyclic groupxe2x80x9d in the definition of Substituents xcex1 has the same meaning as defined above and preferred are imidazolyl, tetrazolyl and pyridinyl groups, of which pyridin-2-yl and pyridin-3-yl groups are particularly preferred.
In the above description, the xe2x80x9cphenyl group substituted with 1 to 5 substituents selected from Substituents xcex1xe2x80x9d in the definition of R4 is a phenyl group substituted with 1 to 5 substituents selected from the group consisting of halogen atoms; hydroxyl groups; C1-6 alkyl groups; halogeno(C1-6 alkyl) groups; C1-6 alkoxy groups; C1-6 alkylthio groups; amino groups which may be substituted with a substituent selected from Substituents xcex3; C3-10 cycloalkyl, C6-10 aryl, C7-16 aralkyl, C6-10 aryloxy, C7-16 aralkyloxy and C6-10 arylthio groups which may each be substituted with 1 to 3 substituents selected from Substituents xcex2; C1-7 aliphatic acyloxy groups; 4- to 7-membered saturated nitrogen-containing heterocyclic groups; 5- or 6-membered aromatic nitrogen-containing heterocyclic groups; nitro groups; and cyano groups. Examples include 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, pentafluorophenyl, 3,5-dichlorophenyl, 2-, 3- or 4-hydroxyphenyl, 3,5-dihydroxyphenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-isopropylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4-s-butylphenyl, 2-, 3- or 4-t-butylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-butoxyphenyl, 2-, 3- or 4-s-butoxyphenyl, 2-, 3- or 4-t-butoxyphenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl, 2-, 3- or 4-isopropylthiophenyl, 2-, 3- or 4-aminophenyl, 3,5-diaminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-(N-ethyl-N-methylamino)phenyl, 2-, 3- or 4-diethylaminophenyl, 2-, 3- or 4-(n-pentylamino)phenyl, 2-, 3- or 4-(n-hexylamino)phenyl, 2-, 3- or 4-phenylaminophenyl, 2-, 3- or 4-benzylaminophenyl, 2-, 3- or 4-formylaminophenyl, 2-, 3- or 4-acetylaminophenyl, 2-, 3- or 4-propionylaminophenyl, 2-, 3- or 4-benzoylaminophenyl, 2-, 3- or 4-(2-, 3- or 4-fluorobenzoylamino)phenyl, 2-, 3- or 4-(2-, 3- or 4-chlorobenzoylamino)phenyl, 2-, 3- or 4-(2,4-difluorobenzoylamino)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-dimethylbenzoylamino)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-di-t-butylbenzoylamino)phenyl, 2-, 3- or 4-(1- or 2-naphthoylamino)phenyl, 2-, 3- or 4-phenylacetylaminophenyl, 2-, 3- or 4-(2-, 3- or 4-fluorophenylacetylamino)phenyl, 2-, 3- or 4-(2-, 3- or 4-chlorophenylacetylamino)phenyl, 2-, 3- or 4-(3-phenyl-propionylamino)phenyl, 2-, 3- or 4-cyclopentanoylaminophenyl, 2-, 3- or 4-cyclohexanoylaminophenyl, 2-, 3- or 4-nicotinoylaminophenyl, 2-, 3- or 4-isonicotinoylaminophenyl, 2-, 3- or 4-(N-acetyl-N-methylamino)phenyl, 2-, 3- or 4-(N-acetyl-N-pentylamino)phenyl, 2-, 3- or 4-(N-acetyl-N-hexylamino)phenyl, 2-, 3- or 4-(N-benzoyl-N-hexylamino)phenyl, 2-, 3- or 4-(N-3-chlorobenzoyl-N-methylamino)phenyl, 2-, 3- or 4-(N-3-chlorobenzoyl-N-hexylamino)phenyl, 2-, 3- or 4-(N-2,4-difluorobenzoyl-N-hexylamino)phenyl, 2-, 3- or 4-[N-(1- or 2-naphthoyl)-N-hexylamino]phenyl, 2-, 3- or 4-(N-hexyl-N-phenylacetylamino)phenyl, 2-, 3- or 4-(N-isobutyl-N-cycloheptanoyl)amino)phenyl, 2-, 3- or 4-(N-butyl-N-nicotinoylamino)-phenyl, 2-, 3- or 4-cyclopentylphenylyl, 2-, 3- or 4-cyclohexylphenylyl, 2-, 3- or 4-(1-adamantyl)phenyl, 2-, 3- or 4-biphenylyl, 2-, 3- or 4-(2xe2x80x2-, 3xe2x80x2- or 4xe2x80x2-hydroxy)-biphenylyl, 2-, 3- or 4-(4-hydroxy-3,5-dimethylphenyl)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-diisopropylphenyl)phenyl, 2-, 3- or 4-(3,5-di-t-butyl-4-hydroxyphenyl)phenyl, 2-, 3- or 4-benzylphenyl, 2-, 3- or 4-(4-hydroxybenzyl)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-dimethylbenzyl)phenyl, 2-, 3- or 4-(3,5-di-t-butyl-4-hydroxybenzyl)phenyl, 2-, 3- or 4-phenoxyphenyl, 2-, 3- or 4-(4-hydroxyphenoxy)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-dimethylphenoxy)phenyl, 2-, 3- or 4-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl, 2-, 3- or 4-benzyloxyphenyl, 2-, 3- or 4-(4-hydroxybenzyloxy)phenyl, 2-, 3- or 4-(4-hydroxy-3,5-dimethylbenzyloxy)phenyl, 2-, 3- or 4-(3,5-di-t-butyl-4-hydroxybenzyloxy)phenyl, 2-, 3- or 4-phenylthiophenyl, 2-, 3- or 4-(4-hydroxyphenylthio)phenyl, 2-, 3- or 4-(3,5-dimethyl-4-hydroxyphenylthio)phenyl, 2-, 3- or 4-(3,5-di-t-butyl-4-hydroxyphenylthio)phenyl, 2-, 3- or 4-formyloxyphenyl, 2-, 3- or 4-acetoxyphenyl, 2-, 3- or 4-propionyloxyphenyl, 2-, 3- or 4-(1-azetidinyl)phenyl 2-, 3- or 4-(1-, 2- or 3-pyrrolidinyl)phenyl, 2-, 3- or 4-(1-, 2-, 3- or 4-piperidinyl)phenyl, 2-, 3- or 4-(2-, 3- or 4-morpholinyl)phenyl, 2-, 3- or 4-(2-, 3- or 4-thiomorpholinyl)phenyl, 2-, 3- or 4-(1- or 2-piperazinyl)phenyl, 2-, 3- or 4-(1-, 2- or 4-imidazolyl)phenyl, 2-, 3- or 4-(teterazol-5-yl)phenyl, 2-, 3- or 4-(2-, 3- or 4-pyridyl)phenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-cyanophenyl, 2- or 3-chloro-4-hydroxyphenyl, 4-chloro-3,5-dihydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl, 2-fluoro-4-hydroxy-3,5-dimethylphenyl, 3-fluoro-5-hydroxy-2,6-dimethylphenyl, 4-fluoro-3-hydroxy-2,5-dimethylphenyl, 2-chloro-4-hydroxy-3,5-dimethylphenyl, 3-chloro-5-hydroxy-2,6-dimethylphenyl, 4-chloro-3-hydroxy-2,5-dimethylphenyl, 2- or 3-amino-4-chlorophenyl, 2,3-dichloro-4-aminophenyl, 2- or 3-chloro-4-methylaminophenyl, 2-hydroxy-3- or 4-methylphenyl, 2-hydroxy-3,4-dimethylphenyl, 3-hydroxy-4- or 5-methylphenyl, 3-hydroxy-2,4-dimethylphenyl, 4-hydroxy-2- or 3-methylphenyl, 2- or 3-ethyl-4-hydroxyphenyl, 4-hydroxy-2- or 3-propylphenyl, 4-hydroxy-2- or 3-isopropylphenyl, 2- or 3-t-butyl-4-hydroxyphenyl, 4-hydroxy-2,3-dimethylphenyl, 4-hydroxy-2,5-dimethylphenyl, 4-hydroxy-3,5-dimethylphenyl, 3,5-diethyl-4-hydroxyphenyl, 3-t-butyl-4-hydroxy-5-methylphenyl, 4-hydroxy-3,5-dipropylphenyl, 4-hydroxy-3,5-diisopropylphenyl, 2,5-di-t-butyl-4-hydroxyphenyl, 3,5-di-t-butyl-4-hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 4-hydroxy-2,3,6-trimethylphenyl, 4-hydroxy-2,3,5,6-tetramethylphenyl, 4-hydroxy-3,5-dimethoxyphenyl, 2- or 3-hydroxy-4-dimethylaminophenyl, 4-benzyl-(2- or 3-hydroxy)phenyl, 3-, 5- or 6-benzyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 3-amino-4-methylphenyl, 4-amino-2,3-dimethylphenyl, 4-amino-2,6-dimethylphenyl, 4-amino-3,5-dimethylphenyl, 4-amino-3,5-diethylphenyl, 4-amino-3,5-dipropylphenyl, 4-amino-3,5-diisopropylphenyl, 4-amino-3,5-di-t-butylphenyl, 4-methylamino-3,5-dimethylphenyl, 4-(N-ethyl-N-methylamino)-3,5-dimethylphenyl, 4-acetylamino-3,5-dimethylphenyl, 4-acetylamino-3,5-di-t-butylphenyl, 4-benzoylamino-3,5-dimethylphenyl, 4-acetoxy-3,5-dimethylphenyl, 4-acetoxy-2,3,5-trimethylphenyl and 3,5-dimethyl-4-nitrophenyl groups.
In the above description, the xe2x80x9cpyridyl group which may be substituted with 1 to 4 substituents selected from Substituents xcex1xe2x80x9d in the definition of R4 is a pyridyl group which may be substituted with 1 to 4 substituents selected from the group consisting of halogen atoms; hydroxyl groups; C1-6 alkyl groups; halogeno(C1-6 alkyl) groups; C1-6 alkoxy groups; C1-6 alkylthio groups; amino groups which may each be substituted with substituents selected from Substituents xcex3; C3-10 cycloalkyl, C6-10 aryl, C7-16 aralkyl, C6-10 aryloxy, C7-16 aralkyloxy and C6-10 arylthio groups which may each be substituted with 1 to 3 substituents selected from Substituents xcex2; C1-7 aliphatic acyloxy groups; 4- to 7-membered saturated nitrogen-containing heterocyclic groups; 5- or 6-membered aromatic nitrogen-containing heterocyclic groups; nitro groups; and cyano groups. Examples include 2-, 3- or 4-pyridyl, 3-, 4-, 5- or 6-fluoro-2-pyridyl, 2-, 4-, 5- or 6-fluoro-3-pyridyl, 2- or 3-fluoro-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 3-, 4-, 5- or 6-bromo-2-pyridyl, 2-, 4-, 5- or 6-bromo-3-pyridyl, 2- or 3-bromo-4-pyridyl, 3-, 4- , 5- or 6-iodo-2-pyridyl, 2-, 4-, 5- or 6-iodo-3-pyridyl, 2- or 3-iodo-4-pyridyl, 3-, 4-, 5- or 6-hydroxy-2-pyridyl, 2-, 4-, 5- or 6-hydroxy-3-pyridyl, 2- or 3-hydroxy-4-pyridyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3,5-dimethyl-4-pyridyl, 3-, 4-, 5- or 6-ethyl-2-pyridyl, 2-, 4-, 5- or 6-ethyl-3-pyridyl, 2- or 3-ethyl-4-pyridyl, 3,5-diethyl-4-pyridyl, 3-, 4-, 5- or 6-propyl-2-pyridyl, 2-, 4-, 5- or 6-propyl-3-pyridyl, 2- or 3-propyl-4-pyridyl, 3,5-dipropyl-4-pyridyl, 3-, 4-, 5- or 6-isopropyl-2-pyridyl, 2-, 4-, 5- or 6-isopropyl-3-pyridyl, 2- or 3-isopropyl-4-pyridyl, 3,5-diisopropyl-4-pyridyl, 3-, 4-, 5- or 6-t-butyl-2-pyridyl, 2-, 4-, 5- or 6-t-butyl-3-pyridyl, 2- or 3-t-butyl-4-pyridyl, 3,5-di-t-butyl-4-pyridyl, 3-, 4-, 5- or 6-trifluoromethyl-2-pyridyl, 2-, 4-, 5- or 6-trifluoromethyl-3-pyridyl, 2- or 3-trifluoromethyl-4-pyridyl, 3-, 4-, 5- or 6-methoxy-2-pyridyl, 2-, 4-, 5- or 6-methoxy-3-pyridyl, 2- or 3-methoxy -4-pyridyl, 3-, 4-, 5- or 6-ethoxy-2-pyridyl , 2-, 4-, 5- or 6-ethoxy-3-pyridyl, 2- or 3-ethoxy-4-pyridyl, 3-, 4-, 5- or 6-propoxy-2-pyridyl, 2-, 4-, 5- or 6-propoxy-3-pyridyl, 2- or 3-propoxy-4-pyridyl, 3-, 4-, 5- or 6-isopropoxy-2-pyridyl, 2-, 4-, 5- or 6-isopropoxy-3-pyridyl, 2- or 3-isopropoxy-4-pyridyl, 3-, 4-, 5- or 6-t-butoxy-2-pyridyl, 2-, 4-, 5- or 6-t-butoxy-3-pyridyl, 2- or 3-t-butoxy-4-pyridyl, 4-methylthio-2-pyridyl, 6-isopropylthio-3-pyridyl, 6-t-butylthio-2-pyridyl, 3-, 4-, 5- or 6-amino-2-pyridyl, 2-, 4-, 5- or 6-amino-3-pyridyl, 2- or 3-amino-4-pyridyl, 3-, 4-, 5- or 6-methylamino-2-pyridyl, 2-, 4-, 5- or 6-methylamino-3-pyridyl, 2- or 3-methylamino-4-pyridyl, 5-phenylamino-2-pyridyl, 5-benzylamino-2-pyridyl, 5-acetylamino-2-pyridyl, 5-benzoylamino-2-pyridyl, 5-phenylacetylamino-2-pyridyl, 6-phenyl-2-pyridyl, 6-(4-hydroxyphenyl)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylphenyl)-2-pyridyl, 6-(3,5-di-t-butyl-4-hydroxyphenyl)-2-pyridyl, 6-benzyl-2-pyridyl, 6-(4-hydroxybenzyl)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylbenzyl)-2-pyridyl, 6-(3,5-di-t-butyl-4-hydroxybenzyl)-2-pyridyl, 6-phenoxy-2-pyridyl, 6-(4-hydroxyphenoxy)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylphenoxy)-2-pyridyl, 6-(3,5-di-t-butyl-4-hydroxyphenoxy)-2-pyridyl, 6-benzyloxy-2-pyridyl, 6-(4-hydroxybenzyloxy)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylbenzyloxy)-2-pyridyl, 6-(3,5-di-t-butyl-4-hydroxybenzyloxy)-2-pyridyl, 6-phenylthio-2-pyridyl, 6-(4-hydroxyphenylthio)-2-pyridyl, 6-(4-hydroxy-3,5-dimethylphenylthio)-2-pyridyl, 6-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-pyridyl, 3-, 4-, 5- or 6-formyloxy-2-pyridyl, 2-, 4-, 5- or 6-formyloxy-3-pyridyl, 2- or 3-formyloxy-4-pyridyl, 3-, 4-, 5- or 6-acetoxy-2-pyridyl, 2-, 4-, 5- or 6-acetoxy-3-pyridyl, 2- or 3-acetoxy-4-pyridyl, 6-(1-pyrrolidinyl)-2-pyridyl, 6-(1-piperidinyl)-2-pyridyl, 6-(4-morpholinyl)-2-pyridyl, 3-, 4-, 5- or 6-nitro-2-pyridyl, 2-, 4-, 5- or 6-nitro-3-pyridyl, 2- or 3-nitro-4-pyridyl, 5-amino-6-fluoro-2-pyridyl, 5-amino-6-chloro-2-pyridyl, 6-chloro-3-nitro-2-pyridyl, 6-methoxy-5-methyl-3-pyridyl, 6-methyl-2-nitro-3-pyridyl, 6-chloro-3-nitro-2-pyridyl, 6-methoxy-3-nitro-2-pyridyl, 6-isopropoxy-3-nitro-2-pyridyl, 6-t-butoxy-3-nitro-2-pyridyl and 6-(4-hydroxy-3,5-dimethylphenoxy)-5-nitro-2-pyridyl groups.
As such a xe2x80x9cpyridyl group which may be substituted with 1 to 4 substituents selected from Substituents xcex1xe2x80x9d, preferred are pyridyl groups which may be substituted with the following substituents (said substituents are halogen atoms, hydroxyl groups, C1-6 alkyl groups, halogeno(C1-6 alkyl) groups, C1-6 alkoxy groups, C1-6 alkylthio groups, amino groups which may be substituted with substituents selected from Substituents xcex3 and nitro groups); more preferred are pyridyl groups which may be substituted with the following substituents (said substituents are fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, ethyl groups, t-butyl groups, trifluoromethyl groups, methoxy groups, amino groups, methylamino groups, dimethylamino groups and nitro groups); and particularly preferred are pyridyl groups.
In the above description, the xe2x80x9cC1-6 alkylene groupxe2x80x9d in the definition of A is a linear or branched C1-6 alkylene group. Examples include methylene, methylmethylene, ethylene, propylene, trimethylene, methylethylene, ethylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramnethylene, 3-methyltetramethylene, 4-methyltetramethylene, propylethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, butylethylene and isobutylethylene, of which C1-4 alkylene groups are preferred, C1-2 alkylene groups are more preferred and methylene groups are most preferred.
The compound (I) of the present invention can be converted into its salt by a conventional method. Examples of such salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts and organic amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-N-phenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminemethane salts; hydrohalogenated salts such as hydrofluoric acid salts, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; lower alkanesulfonate salts such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; arylsulfonate salts such as benzensulfonates and p-toluenesulfonates; organic acid salts such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates and maleates; and amino acid salts such as omithinates, glutamates and aspartates, of which hydrohalogenated salts and organic acid salts are preferred.
When the compound (I) of the present invention is left in air or is recrystallized, it can absorb water or has adsorbed water attached on the surface and sometimes becomes a hydrate. In addition, the compound (I) of the present invention can absorb other solvents and form their solvates. Such solvates (including hydrates) are embraced in the present invention and are included when reference is made to a substituted fused heterocyclic compound (I) or a pharmacologically acceptable salt thereof.
Furthermore, compounds which are converted under physiological conditions into the corresponding compound (I) or a pharmacologically acceptable salt thereof, that is, so-called prodrugs are also embraced in the present invention.
Incidentally, the compound (I) of the present invention has various isomers.
Described specifically, when R3 represents a 2,4-dioxothiazolidin-5-ylmethyl group (IV-2) or 2,4-dioxooxazolidin-5-ylmethyl (IV-3), the thiazolidine or oxazolidine ring of it has an asymmetric carbon atom at the 5-position so that there exist stereoisomers in the R-form and S-form. Each of the stereoisomers and a mixture composed of the stereoisomers at any ratio are all embraced in the present invention. In the case of such a stereoisomer, the compound (I) can be synthesized from optically resolved raw materials or the synthesized compound (I) can be optically resolved, if necessary, by a conventional optical resolution method or separation method.
When in the compound (I) of the present invention, R3 represents a 2,4-dioxothiazolin-5-ylmethyl group (IV-2), 2,4-dioxooxazolidin-5-ylmethyl group (IV-3) or 3,5-dioxooxadiazolidin-2-ylmethyl group (IV-4), it is presumed to exist as various tautomers and each of them or a mixture of them at any ratio are all embraced in the present invention. Such isomers are, for example, as illustrated below: 
Examples of medicaments which may form a pharmaceutical composition, when used in combination with a compound (I) of the present invention or a pharmacologically acceptable salt thereof include xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
In the above description, an xcex1-glucosidase inhibitor is a medicament having action in inhibiting a digestive enzyme such as amylase, maltase, xcex1-dextrinase or sucrase, thereby retarding the digestion of starch or sucrose. Examples of them include acarbose, N-(1,3-dihydroxy-2-propyl)variolamine (common name: voglibose) and miglitol.
In the above description, an aldose reductase inhibitor is a medicament which inhibits a rate-limiting enzyme of the first step of the polyol pathway, thereby inhibiting diabetic complications. Examples include tolrestat, epalrestat, 2,7-difluoro-spiro(9H-fluoren-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (common name: imirestat), 3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinozolineacetic acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2,5xe2x80x2-dioxo-spiro[4H-1-benzopyran-4,4xe2x80x2-imidazolidine]-2-carboxamide (SNK-860), zopolrestat, sorbinil and 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209).
In the above description, a biguanide preparation is a medicament having effects in anaerobic glycolysis promotion, insulin action reinforcement at the periphery, intestinal glucose absorption inhibition, hepatic gluconeogenesis inhibition and fatty-acid oxidation inhibition and examples include phenformin, metformin and buformin.
In the above description, a statin base compound is a medicament which inhibits hydroxymethylglutaryl CoA (HMG-CoA) reductase, thereby lowering the blood cholesterol level and examples include pravastatin and the sodium salt thereof, simvastatin, lovastatin, atorvastatin and fluvastatin.
In the above description, a squalene synthesis inhibitor is a medicament for inhibiting squalene synthesis, thereby lowering the blood cholesterol level and examples include monopotassium (S)-xcex1-[bis(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl-3-phenoxybenzenebutanesulfonate (BMS-188494).
In the above description, a fibrate base compound is a medicament for inhibiting synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase, thereby lowering the triglyceride level in the blood. Examples include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate and theofibrate.
In the above description, a LDL catabolism promoter is a medicament for increasing LDL (low-density lipoprotein) receptors, thereby lowering the blood cholesterol level and examples include compounds described in Japanese Patent Application Kokai Hei 7-316144 or salts thereof, more specifically, N-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienoic amide.
The above-described statin base compounds, squalene synthesis inhibitors, fibrate base compounds and LDL catabolism promoters can be replaced with another chemical effective for lowering the blood cholesterol or triglyceride level. Examples of such a medicament include nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol; and ion exchange resin preparations such as cholestyramine.
In the above description, an angiotensin-converting enzyme inhibitor is a medicament for inhibiting angiotensin-converting enzyme, thereby lowering the blood pressure and at the same time, partially lowering the blood sugar level of a patient suffering from diabetes. Examples include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronaprilI cilazapril, enalaprilat, fosinopril, moveltipril, perindopril, quinapril, spirapril, temocapril and trandolapril.
In reference to the compound (I) of the present invention, preferred examples include:
(1) compounds wherein R1 represents a group of the formula (II),
(2) compounds wherein R2 and R5 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6 alkyl group, a halogeno(C1-6 alkyl) group, a C1-6 alkoxy group, a C1-6 alkylthio group or an amino group which may be substituted with substituents selected from Substituents xcex3,
(3) compounds wherein R2 and R5 are the same or different and each represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a methylthio group or an amino group,
(4) compounds wherein R2 and R5 each represent a hydrogen atom,
(5) compounds wherein R3 represents a group of any one of the formulas (IV-1) to (IV-3),
(6) compounds wherein R3 represents a group of the formula (IV-2) or (IV-3),
(7) compounds wherein R3 represents a group of the formula (IV-2),
(8) compounds wherein R4 represents a pyridyl group which may be substituted with one substituent described below (the substituent is a halogen atom, a hydroxyl group, a C1-6 alkyl group, a halogeno(C1-6 alkyl) group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group which may be substituted with substituents selected from Substituents xcex3, or a nitro group),
(9) compounds wherein R4 represents a pyridyl group which may be substituted with one substituent described below (the substituent is a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a t-butyl group, a trifluoromethyl group, a methoxy group, a methylthio group, an amino group, a methylamino group, a dimethylamino group or a nitro group),
(10) compounds having as R4 a pyridyl group,
(11) compounds wherein R4 is a phenyl group substituted with at least one substituent selected from the following substituents (the substituents consist of C3-10 cycloalkyl, C6-10 aryl and C7-16 aralkyl groups each of which may be substituted with 1 to 3 substituents selected from Substituents xcex2, 4- to 7-membered saturated nitrogen-containing heterocyclic groups and 5- or 6-membered aromatic nitrogen-containing heterocyclic groups),
(12) compounds wherein R4 is a phenyl group substituted with one substituent described below (the substituent is a C3-10 cycloalkyl, C6-10 aryl or C7-16 aralkyl group which may be substituted with one substituent selected from Substituents xcex2, a 4- to 7-membered saturated nitrogen-containing heterocyclic group or a 5- or 6-membered aromatic nitrogen-containing heterocyclic group,
(13) compounds wherein R4 is a phenyl group substituted with one substituent described below (the substituent is a C3-10 cycloalkyl, C6-10 aryl or C7-16 aralkyl group which may be substituted with a halogen atom, hydroxyl group, C1-6 alkyl group, halogeno(C1-6 alkyl) group, C1-6 alkoxy group or amino group which may be substituted with substituents selected from Substituents xcex3, a 4- to 7-membered saturated nitrogen-containing heterocyclic group, or a 5- or 6-membered aromatic nitrogen-containing heterocyclic group),
(14) compounds wherein R4 is a phenyl group substituted with one substituent described below (the substituent is a phenyl or benzyl group which may be substituted with a halogen atom, hydroxyl group, C1-6 alkyl group, halogeno(C1-6 alkyl) group, C1-6 alkoxy group or amino group which may be substituted with substituents selected from Substituents xcex3, an adamantyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, an imidazolyl group, a tetrazolyl group or a pyridinyl group),
(15) compounds wherein R4 is a phenyl group substituted with one substituent described below (the substituent is a phenyl or benzyl group which may be substituted with a fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, t-butyl group, trifluoromethyl group, methoxy group, amino group, methylamino group or dimethylamino group, an adamantyl group, a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, an imidazolyl group, a tetrazolyl group or a pyridinyl group),
(16) compounds wherein R4 is a 4-biphenylyl, 4-benzylphenyl, 4xe2x80x2-hydroxybiphenylyl, (pyrrolidin-1-yl)phenyl, (morpholin-4-yl)phenyl, (piperidin-1-yl)phenyl, (pyridin-2-yl)phenyl, (pyridin-3-yl)phenyl or 4-(1-adamantyl)phenyl group,
(17) compounds wherein R4 is a phenyl group which is substituted with one acylamino group, wherein the amino moiety may be substituted with a further substituent selected from Substituents xcex3, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy and C1-6 alkylthio groups),
(18) compounds wherein R4 is a phenyl group which is substituted with one acylamino group, wherein the amino moiety may be substituted with a substituent selected from Substituents xcex3, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and C1-6 alkyl groups),
(19) compounds wherein R4 is a phenyl group which is substituted with one acylamino group, wherein the amino moiety may be further substituted with a C1-10 alkyl group or a C7-12 aralkyl group which may have substituents, and said phenyl group may be further substituted with 1 to 3 C1-6 alkyl groups),
(20) compounds wherein R4 is a phenyl group which is substituted with one substituent described below (the substituent is a C7-11 aromatic acylamino, C4-11 cycloalkylcarbonylamino or 5- or 6-membered aromatic nitrogen-containing heterocyclic carbonylamino group which may have substituents),
(21) compounds wherein R4 is a phenyl group substituted with a benzoylamino, 3-chlorobenzoylamino, 2,4-difluorobenzoylamino, 4-hydroxy-3,5-di-t-butylbenzoylamino, naphthoylamino, cyclopentanoylamino, cyclohexanoylamino, nicotinoylamino, isonicotinoylamino, N-acetyl-N-hexylamino or adamantylcarbonylamino group,
(22) compounds wherein R4 is a phenyl group which is substituted with one amino, amino substituted with 1 or 2 substituents (the substituents are the same or different and each is a group selected from C1-10 alkyl, and C6-10 aryl and C7-16 aralkyl each of which may have substituents), nitro or cyano group, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy and C1-6 alkylthio groups),
(23) compounds wherein R4 is a phenyl group which is substituted with one amino, mono- or di-(C1-10 alkyl)amino, or cyano group and at the same time, may be substituted with 1 or 2 C1-6 alkyl groups,
(24) compounds wherein R4 is a 4-aminophenyl, 4-amino-3,5-dimethylphenyl, 4-amino-3,5-di-t-butylphenyl, 3- or 4-dimethylaminophenyl or 4-cyanophenyl group,
(25) compounds wherein R4 is a phenyl group which is substituted with one C6-10 aryloxy, C7-16 aralkyloxy or C6-10 arylthio group which may be substituted with 1 to 3 substituents selected from Substituents xcex2, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy and C1-6 alkylthio groups),
(26) compounds wherein R4 is a phenyl group which is substituted with a C6-10 aryloxy which may be substituted with 1 to 3 substituents selected from Substituents xcex2, and said phenyl group may be further substituted with 1 to 2 C1-6 alkyl groups,
(27) compounds wherein R4 is a phenyl group substituted with a C6-10 aryloxy group which may be substituted with one substituent selected from Substituents A,
(28) compounds wherein R4 is a 4-phenoxyphenyl group,
(29) compounds wherein R4 is a phenyl group substituted with 1 to 5 substituents selected from the following substituents (the substituents consist of halogen atoms and hydroxyl, C1-6 alkyl, halogeno(C1-6 alkyl), C1-6 alkoxy, C1-6 alkylthio and C1-7 aliphatic acyloxy groups),
(30) compounds wherein R4 is a phenyl group which is substituted with one halogen atom, hydroxyl group, C1-6 alkyl group, halogeno(C1-6 alkyl) group, C1-6 alkoxy group, C1-6 alkylthio group or C1-7 aliphatic acyloxy group, and said phenyl group may be further substituted with 1 to 4 substituents selected from the following substituents (the substituents consist of halogen atoms and C1-6 alkyl and halogeno(C1-6 alkyl) groups),
(31) compounds wherein R4 is a phenyl group substituted with one C1-6 alkyl group, halogeno(C1-6 alkyl) group, C1-6 alkoxy group or C1-6 alkylthio group or with 1 to 5 halogen atoms,
(32) compounds wherein R4 is a phenyl group substituted with one halogeno(C1-2 alkyl), C1-2 alkoxy or C1-2 alkylthio group or with 1 to 5 fluorine atoms or chlorine atoms,
(33) compounds wherein R4 is a 4-trifluoromethylphenyl, 4-methylthiophenyl, 4-methoxyphenyl or pentafluorophenyl group,
(34) compounds wherein R4 is a phenyl group which is substituted with one hydroxyl or C1-7 aliphatic acyloxy group, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and C1-6 alkyl groups),
(35) compounds wherein R4 is a phenyl group which is substituted with one hydroxyl group, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and C1-6 alkyl groups),
(36) compounds wherein R4 is a phenyl group which is substituted with one hydroxyl group, and said phenyl group may be further substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of fluorine and chlorine atoms and methyl and t-butyl groups),
(37) compounds wherein R4 is a 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-3,5-di-t-butylphenyl, 4-hydroxy-2,3,5-trimethylphenyl or 2-chloro-4-hydroxy-3,5-dimethylphenyl group,
(38) compounds wherein R6 is a hydrogen atom, a C1-6 alkyl group, or a phenyl or benzyl group which may be substituted with 1 to 3 substituents selected from the following substituents (the substituents consist of halogen atoms and hydroxyl, C1-6 alkyl and halogeno(C1-6 alkyl) groups),
(39) compounds wherein R6 is a hydrogen atom, a C1-4 alkyl group, or a phenyl or benzyl group which may be substituted with one substituent described below (the substituent is a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group or an ethyl group),
(40) compounds wherein R6 is a hydrogen atom or a C1-4 alkyl group,
(41) compounds wherein R6 is a C1-2 alkyl group,
(42) compounds wherein R6 is a methyl group,
(43) compounds wherein A is a C1-4 alkylene group,
(44) compounds wherein A is a C1-2 alkylene group,
(45) compounds wherein A is a methylene group,
(46) compounds wherein B is an oxygen atom,
(47) compounds wherein D is an oxygen atom,
(48) compounds wherein D is a sulfur atom,
(49) compounds wherein E is a CH group, and
(50) compounds wherein E is a nitrogen atom.
Any combinations of two to nine groups selected from (1), (2)-(4), (5)-(7), (8)-(37), (38)-(42), (43)-(45), (46), (47)-(48) and (49)-(50) are also preferred.
Some compounds of the present invention are shown in Tables 1-10. It should however be borne in mind that the present invention is not limited to them. Compounds in Tables 1 to 10 each have the structural formula of (I-1) to (I-10) and abbreviations in the tables are as follows:
Ac: acetyl group
Ada(1): 1-adamantyl group
Bu: butyl group
sBu: s-butyl group
tBu: t-butyl group
Bz: benzyl group
Et: ethyl group
Hx: hexyl group
cHx: cyclohexyl group
Imid(1): 1-imidazolyl group
Me: methyl group
Mor(4): 4-morpholinyl group
Np(1): 1-naphthyl group
Np(2): 2-naphthyl group
Ph: phenyl group
Pip(1): 1-piperidyl group
Pipra(1): 1-piperazinyl group
Pn: pentyl group
cPn: cyclopentyl group
Pr: propyl group
iPr: isopropyl group
Pyr(2): 2-pyridyl group
Pyr(3): 3-pyridyl group
Pyr(4): 4-pyridyl group
Pyrd(1): 1-pyrrolidinyl group
TioMor(4): 4-thiomorpholinyl group
Tz: tetrazol-5-yl group
Most preferred examples of the compound include:
Compound No. 1-70: 5-{4-[6-(4-hydroxyphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-131: 5-{4-[1-methyl-6-(4-trifluoromethylphenoxy)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-132: 5-{4-[1-methyl-6-(4-methoxyphenoxy)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-136: 5-{4-[1-methyl-6-(4-methylthiophenoxy)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-142: 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-153: 5-{4-[6-(3-dimethylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-164: 5-{4-[6-(4-acetylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-169: 5-{4-[1-methyl-6-(4-phenylphenoxy)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-171: 5-{4-[6-(4xe2x80x2-hydroxybiphenyl-4-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-184: 5-{4-[6-(4-benzylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-199: 5-{4-(6-[2-(pyrrolidin-1-yl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-241: 5-{4-(6-[2-(piperidin-1-yl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-284: 5-{4-(6-[2-(morpholin-4-yl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-292: 5-{4-(1-methyl-6-[3-(morpholin-4-yl)phenoxy]-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-368: 5-{4-[6-(2-chloro-4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-481: 5-{4-[6-(4-hydroxy-2-methylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-486: 5-{4-[6-(4-hydroxy-3-methylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-513: 5-{4-[6-(4-hydroxy-2,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-520: 5-{4-[6-(4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-593: 5-{4-[6-(3,5-di-t-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-595: 5-{4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-650: 5-{4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-651: 5-{4-[5-(4-hydroxy-2,3,5-trimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-739: 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-808: 5-{4-[6-(4-acetylamino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-821: 5-{4-[6-(pyridin-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-823: 5-{4-[1-methyl-6-(pyridin-2-ylthio)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-938: 5-{4-[1-methyl-6-(pyridin-3-yloxy)-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1126: 5-{4-(6-[4-(imidazol-1-yl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-1182: 5-{4-(6-[4-(1-adamantyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl}thiazolidine-2,4-dione,
Compound No. 1-1210: 5-{4-[6-(4-cyanophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1234: 5-{4-[6-(2,5-di-t-butyl-4-hydroxyphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1235: 5-{4-[6-(pentafluorophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1248: 5-{4-[6-(4-benzoylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1263: 5-[4-{6-[4-(2,4-difluorobenzoylamino)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy}benzyl]thiazolidine-2,4-dione,
Compound No. 1-1292: 5-{4-[6-(4-cyclopentanecarbonylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione,
Compound No. 1-1305: 5-{4-[6-(4-nicotinoylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione, and
Compound No. 5-135: 5-{4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzylidene}thiazolidine-2,4-dione.
The compound of the present invention represented by the formula (I) can be prepared easily in accordance with any one of the following methods: 
In the above reaction scheme, R1, R2, A and B have the same meanings as described above; R1a represents a similar group to that defined as the group R1 except that any amino and/or hydroxyl group contained in R1 is an amino and/or hydroxyl group which may be protected by an amino- and/or hydroxyl-protecting group; R2a represents a similar group to that as defined as the group R2 except that any amino and/or hydroxyl group contained in R2 is an amino and/or hydroxyl group which may be protected by an amino- and/or hydroxyl-protecting group; R3a represents the following group: 
(wherein, R8 represents a triphenylmethyl group); and R3b represents the following group: 
In the above description, there is no particular limitation on the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9cthe amino group which may be protected by an amino-protecting groupxe2x80x9d in R1a and R2a provided that it is an amino-protecting group used in the field of organic synthetic chemistry. Examples include xe2x80x9caliphatic acyl groupsxe2x80x9d, for example, the above-exemplified C1-7 aliphatic acyl groups, halogeno(C2-7 alkyl)carbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups and C2-7 alkylcarbonyl groups substituted with C1-6 alkoxy groups such as methoxyacetyl groups; xe2x80x9caromatic acyl groupsxe2x80x9d, for example, the above-exemplified C7-11 aromatic acyl groups, halogeno(C7-11 aromatic acyl) groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups, C7-11 aromatic acyl groups substituted with C1-6 alkyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, C7-11 aromatic acyl groups substituted with C1-6 alkoxy groups such as 4-anisoyl, C7-11 aromatic acyl groups substituted with nitro groups such as 4-nitrobenzyol groups and 2-nitrobenzyol groups, C7-11 aromatic acyl groups substituted with C2-7 alkoxycarbonyl groups such as 2-(methoxycarbonyl)-benzoyl groups and C7-11 aromatic acyl groups substituted with C6-10 aryl groups such as 4-phenylbenzoyl groups; xe2x80x9calkoxycarbonyl groupsxe2x80x9d, for example, the above-exemplified C2-7 alkoxycarbonyl groups and C2-7 alkoxycarbonyl groups substituted with halogen or tri(C1-6 alkyl)silyl groups such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; xe2x80x9calkenyloxycarbonyl groupsxe2x80x9d such as vinyloxycarbonyl groups and allyloxycarbonyl groups; xe2x80x9caralkyloxycarbonyl groups having an aryl ring which may be substituted with 1 or 2 C1-6 alkoxy or nitro groupsxe2x80x9d such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups; xe2x80x9csilyl groupsxe2x80x9d, for example, tri(C1-6 alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups and silyl groups substituted with three substituents selected from aryl and C1-6 alkyl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; xe2x80x9caralkyl groupsxe2x80x9d, for example, C1-6 alkyl groups substituted with 1 to 3 aryl groups such as benzyl, phenethyl, 3-pheylpropyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl groups and C1-6 alkyl groups substituted with 1 to 3 aryl groups having an aryl ring substituted with C1-6 alkyl, C1-6 alkoxy or nitro groups, halogen atoms or cyano groups such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl and piperonyl groups; and xe2x80x9csubstituted methylene groups each of which forms a Schiff basexe2x80x9d such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene and (5-chloro-2-hydroxyphenyl)phenylmethylene groups, of which the C1-7 aliphatic acyl groups, C7-11 aromatic acyl groups and C2-7 alkoxycarbonyl groups are preferred and the C2-7 alkoxycarbonyl groups are more preferred and the t-butoxycarbonyl group is most preferred.
In the above description, there is no particular limitation on the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9chydroxyl group which may be protected by a hydroxyl-protecting groupxe2x80x9d in R1a and R2a provided that it is a hydroxyl-protecting group used in the field of organic synthetic chemistry. Examples include xe2x80x9caliphatic acyl groupsxe2x80x9d, for example, the above-exemplified C1-7 aliphatic acyl groups, C2-7 alkylcarbonyl groups substituted with carboxy groups such as succinoyl, glutaroyl and adipoyl groups, halogeno(C2-7 alkyl)carbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups and C2-7 alkylcarbonyl groups substituted with C1-6 alkoxy groups such as methoxyacetyl groups; xe2x80x9caromatic acyl groupsxe2x80x9d, for example, the above-exemplified C7-11 acyl groups, halogeno(C7-11 aromatic acyl) groups such as 2-bromobenzoyl and 4-chlorobenzyol groups, C7-11 aromatic acyl groups substituted with C1-6 alkyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl groups, C7-11 aromatic acyl groups substituted with C1-6 alkoxy groups such as 4-anisoyl groups, C7-11 aromatic acyl groups substituted with carboxy groups such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl groups, C7-11 aromatic acyl groups substituted with nitro groups such as 4-nitrobenzoyl and 2-nitrobenzoyl groups, C7-11 aromatic acyl groups substituted with C2-7 alkoxycarbonyl groups such as 2-(methoxycarbonyl)benzoyl groups and C7-11 aromatic acyl groups substituted with C6-10 aryl groups such as 4-phenylbenzoyl groups; xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupsxe2x80x9d such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupsxe2x80x9d such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups; xe2x80x9csilyl groupsxe2x80x9d, for example, tri(C1-6 alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups and silyl groups substituted with 3 substituents selected from aryl and C1-6 alkyl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; xe2x80x9calkoxymethyl groupsxe2x80x9d, for example, (C1-6 alkoxy)methyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups, (C1-6 alkoxy)methyl groups substituted with C1-6 alkoxy groups such as 2-methoxyethoxymethyl groups and halogeno(C1-6 alkoxy)methyl groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; xe2x80x9csubstituted ethyl groupsxe2x80x9d, for example, (C1-6 alkoxy)ethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl groups and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; xe2x80x9caralkyl groupsxe2x80x9d, for example, C1-6 alkyl groups substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl groups and C1-6 alkyl groups substituted with 1 to 3 aryl groups having an aryl ring substituted with C1-6 alkyl or C1-6 alkoxy groups, halogen atoms or cyano groups such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl and piperonyl groups; xe2x80x9calkoxycarbonyl groupsxe2x80x9d such as the above-exemplified C2-7 alkoxycarbonyl groups and C2-7 alkoxycarbonyl groups substituted with halogen atoms or tri(C1-6 alkyl)silyl groups such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; xe2x80x9calkenyloxycarbonyl groupsxe2x80x9d such as vinyloxycarbonyl and allyloxycarbonyl groups; and xe2x80x9caralkyloxycarbonyl groupsxe2x80x9d having an aryl ring which may be substituted with 1 to 2 C1-6 alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups, of which the C1-7 aliphatic acyl, C7-11 aromatic acyl, C2-7 alkoxycarbonyl and (C1-6 alkoxy)methyl groups are preferred, the C7-11 aromatic acyl and (C1-6 alkoxy)methyl groups are more preferred and the benzoyl and methoxymethyl groups are most preferred.
Method A is a process for the preparation of Compound (Ia), which is Compound (I) wherein R3 is selected from a group of the formula (IV-1) to (IV-4).
Step A1 is a step for preparing the compound of formula (VII) by reacting a compound of the formula (Vxe2x80x2) with a compound of formula (VI) in an inert solvent in the presence of a phosphine (preferably, tributylphosphine or triphenylphosphine) and an azodicarboxylic acid compound (preferably, diethyl azodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine).
There is no particular limitation on the nature of the inert solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers and mixtures of these solvents are preferred (more preferred are the aromatic hydrocarbons and ethers and particularly preferred are toluene and tetrahydrofuran).
The reaction temperature depends on the natures of the raw materials and solvent and the like, however, it usually ranges from xe2x88x9220xc2x0 C. to 150xc2x0 C. (preferably from 0xc2x0 C. to 60xc2x0 C.).
The reaction time depends on the natures of the raw materials and solvent, the reaction temperature and the like, however, it usually ranges from 30 minutes to 5 days (preferably from 5 hours to 72 hours).
After the completion of the reaction, the resulting compound (VII) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by removing the insoluble matter from the reaction mixture by filtration; adding to the filtrate an organic solvent, which is not miscible with water such as ethyl acetate, separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The product so obtained can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation or chromatography.
Step A2 is a step for preparing a compound of formula (Ia) by reacting Compound (VII) with an acid in the presence or absence (preferably, in the presence) of an inert solvent, thereby removing the triphenylmethyl group of R8, and then removing the amino- and/or hydroxyl-protecting group in R1a and R2a if necessary.
There is no particular limitation on the nature of the acid to be employed for the former stage of the reaction, provided that it is used in ordinary reactions as an acid catalyst. Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid; Brxc3x8nsted acids, for example, organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride and boron tribromide; and acidic ion exchange resins, of which inorganic and organic acids (particularly, hydrochloric acid, acetic acid and trifluoroacetic acid) are preferred.
There is no particular limitation on the nature of the inert solvent to be used in the former stage of the reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; and mixtures of the above-exemplified solvents, of which ethers, alcohols and water (particularly, dioxane, tetrahydrofuran, ethanol and water) are preferred.
The reaction temperature depends on the natures of the raw material, acid and solvent, and the like, however, it usually ranges from xe2x88x9220xc2x0 C. to the boiling point (preferably from 0xc2x0 C. to 100xc2x0 C.).
The reaction time depends on the natures of the raw material, acid and solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).
In this step, the target compound (Ia) can also be prepared by subjecting Compound (VII) to catalytic reduction in an inert solvent under atmospheric pressure or under pressure (preferably under pressure), thereby removing the triphenylmethyl group of R8, and then removing the protecting group of the amino group and/or hydroxyl group in R1a and R2a as needed.
There is no particular limitation on the nature of the catalyst to be used in the above catalytic reduction, provided that it is used in ordinary catalytic reductions. Examples include palladium-carbon, Raney nickel, rhodium-aluminum oxide, triphenylphosphine-rhodium oxide, palladium-barium sulfate, palladium black, platinum oxide and platinum black, of which palladium-carbon is preferred.
There is no particular limitation on the nature of the inert solvent to be used in the above catalytic reduction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; organic acids such as acetic acid and trifluoroacetic acid; and mixtures of the above-exemplified solvents, of which ethers, alcohols and organic acids (particularly, alcohols) are preferred.
The reaction temperature depends on the natures of the raw material, catalyst and solvent to be used and the like, however, it usually ranges from 0xc2x0 C. to 100xc2x0 C. (preferably from 10xc2x0 C. to 50xc2x0 C.).
The reaction time depends on the natures of the raw material, catalyst and solvent to be used, the reaction temperature and the like, however, it usually ranges from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).
The removal of the protecting group of the amino group or hydroxyl group depends on its nature, however, it is generally carried out as described below in accordance with a method known in the field of Organic synthetic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley and Sons or J. F. W. McOmis, (Protective Groups in Organic Chemistry), Plenum Press.
When the amino-protecting group is a silyl group, it can be removed by treating with a fluorine-anion-forming compound such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride.
There is no particular limitation on the nature of the solvent to be employed for the above reaction, provided that it has no adverse effect on the reaction. Preferred examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether.
Although no particular limitation is imposed on the reaction temperature and reaction time, the reaction is ordinarily carried out at a temperature of from 0 to 50xc2x0 C. for 10 to 18 hours.
When the amino-protecting group is an aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or substituted methylene group forming a Schiff base, it can be removed by treating with an acid or base in the presence of an aqueous solvent.
There is no particular limitation on the nature of the acid used in the above reaction, provided that it is ordinarily used as an acid and has no adverse effect on the reaction. Examples include inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid and nitric acid, of which hydrochloric acid is preferred.
There is no particular limitation imposed on the nature of the base to be employed in the above reaction provided that it has no adverse effects on the other part of the compound. Preferred examples include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium-t-butoxide; and ammonia such as aqueous ammonia and concentrated ammonia-methanol.
There is no particular limitation on the nature of the solvent to be used in the above reaction provided that it can be used in ordinary hydrolysis. Examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; water; and mixtures of water and the above-exemplified organic solvents, of which the ethers (particularly dioxane) are preferred.
There is no particular limitation on the reaction temperature and reaction time, and they depend on the natures of the starting substance, solvent and acid or base to be employed. The reaction is usually carried out at a temperature of from 0 to 150xc2x0 C. for 1 to 10 hours in order to suppress side reactions.
When the amino-protecting group is an aralkyl or aralkyloxycarbonyl group, it is preferably removed by contact with a reducing agent (preferably catalytic reduction in the presence of a catalyst at room temperature) in an inert solvent or by using an oxidizing agent.
There is no particular limitation on the nature of the solvent to be used for the removal by catalytic reduction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; organic acids such as acetic acid; water; and mixed solvents of water and the above-exemplified solvents, of which alcohols, ethers, organic acids and water (particularly, alcohols and organic acids) are preferred.
There is no particular limitation on the nature of the catalyst to be used provided that it is usually employed for catalytic reductions. Preferred examples include palladium-carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate.
Although no particular limitation is imposed on the pressure, the reaction is usually carried out at a pressure of from 1 to 10 atm.
Although the reaction temperature and reaction time depend on the natures of the raw material, catalyst and solvent, and the like, the reaction is usually carried at a temperature of from 0 to 100xc2x0 C. for 5 minutes to 24 hours.
There is no particular limitation on the nature of the solvent used for the removal by oxidation provided that it has no adverse effect on the present reaction. Water containing organic solvents are preferably employed.
Examples of such an organic solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; and sulfolane, of which the halogenated hydrocarbons, ethers and sulfoxides (particularly, the halogenated hydrocarbons and sulfoxides) are preferred.
There is no particular limitation on the oxidizing agent to be used provided that it is ordinarily used in oxidations. Preferred examples include potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Although the reaction temperature and reaction time depend on the natures of the raw material, catalyst and solvent, and the like, the reaction is usually carried out at a temperature of from 0 to 150xc2x0 C. for 10 minutes to 24 hours.
When the amino-protecting group is an alkenyloxycarbonyl group, it can be usually removed by treating with a base under similar conditions to those employed when the amino-protecting group is the above-described aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or substituted methylene group forming a Schiff base.
Incidentally, when the protecting group is an allyloxycarbonyl group, it can be removed conveniently with less side reactions by using, in particular, palladium and triphenylphosphine or nickel tetracarbonyl.
When a silyl group is used as the hydroxyl-protecting group, it can usually be removed by treating with a fluorine-anion-forming compound such as tetrabutyl ammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride; or by treating with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.
Incidentally, when the removal of the silyl group is carried out using a fluoride ion, the reaction happens to be accelerated by the addition of an organic acid such as formic acid, acetic acid or propionic acid.
There is no particular limitation on the nature of the inert solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Preferred examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water; and mixtures of the above-exemplified solvents.
Although the reaction temperature and reaction time depend on the natures of the raw material, catalyst and solvent, and the like, the reaction is usually carried at a temperature of from 0 to 100xc2x0 C. (preferably from 10 to 50xc2x0 C.) for 1 hour to 24 hours.
When the hydroxyl-protecting group is an aralkyl or aralkyloxycarbonyl group, it is usually preferred to remove the protecting group by contact with a reducing agent (preferably, catalytic reduction at room temperature in the presence of a catalyst) or by using an oxidizing agent, in an inert solvent.
There is no particular limitation on the nature of the solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; and mixtures of the above-exemplified solvents, of which alcohols (particularly, methanol) are preferred.
There is no particular limitation on the nature of the catalyst to be used provided that it is usually employed for catalytic reduction. Examples include palladium-carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate, of which the palladium-carbon is preferred.
Although no particular limitation is imposed on the pressure, the reaction is usually carried out under a pressure from 1 to 10 atm.
Although the reaction temperature and reaction time depend on the natures of the raw materials, catalyst and solvent, and the like, the reaction is usually carried out at a temperature of from 0 to 100xc2x0 C. (preferably from 20 to 70xc2x0 C.) for 5 minutes to 48 hours (preferably from 1 to 24 hours).
There is no particular limitation on the nature of the solvent to be used for the removal by oxidation provided that it has no adverse effect on the present reaction. Water-containing organic solvents are preferred as the solvent.
Specific examples of such an organic solvent include ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide.
There is no particular limitation on the oxidizing agent to be used, provided that it is ordinarily used in oxidation. Preferred examples include potassium persulfate, sodium persulfate, cerium ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).
Although the reaction temperature and reaction time depend on the natures of the raw materials, catalyst and solvent, and the like, the reaction is usually carried at a temperature of from 0 to 150xc2x0 C. for 10 minutes to 24 hours.
The protecting group can also be removed by treating with an alkali metal such as metal lithium or metal sodium in liquid ammonia or an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methyl cellosolve at xe2x88x9278 to 0xc2x0 C.
The protecting group can also be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.
There is no particular limitation on the nature of the solvent to be used provided that it has no adverse effect on the present reaction. Preferred examples include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; and mixtures of the above-exemplified solvents.
Although the reaction temperature and reaction time depend on the natures of the raw materials and solvent, and the like, the reaction is usually carried out at a temperature of from 0 to 50xc2x0 C. for 5 minutes to 72 hours.
Incidentally, when the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.
When the hydroxyl-protecting group is an aliphatic acyl, aromatic acyl or alkoxycarbonyl group, it can be removed by treating with a base in a solvent.
There is no particular limitation on the base to be used in the above reaction provided that it has no adverse effect on the remainder of the compound. Preferred examples include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; and ammonia such as aqueous ammonia and concentrated ammonia-methanol, of which the alkali metal hydroxides, metal alkoxides and ammonia (particularly, the alkali metal hydroxides and metal alkoxides) are preferred.
There is no particular limitation on the nature of the solvent to be used in the above reaction provided that it can be used in ordinary hydrolysis. Examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; and mixtures of the above-exemplified organic solvents.
There is no particular limitation on the reaction temperature and reaction time, they depend on the natures of the raw materials, base and solvent, and the like. The reaction is usually carried out at a temperature of from xe2x88x9220 to 150xc2x0 C. for 1 to 10 hours in order to suppress side reactions.
When the hydroxyl-protecting group is an alkoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or substituted ethyl group, it is usually removed by treating with an acid in a solvent.
There is no particular limitation on the acid to be used in the above reaction, provided that it is usually employed as a Brxc3x8nsted acid or Lewis acid. Preferred examples include Brxc3x8nsted acids, for example, hydrogen chloride, inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, and Lewis acids such as boron trifluoride. A strong acidic cation exchange resin such as Dowex 50W can also be employed.
There is no particular limitation on the nature of the solvent to be used for the above reaction, provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; hydrogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexane; water; and mixed solvents of the above-exemplified solvents, of which the ethers (particularly tetrahydrofuran) and the alcohols (particularly methanol) are preferred.
Although the reaction temperature and reaction time depend on the raw materials, acid and solvent, and the like, the reaction is usually carried out at a temperature of from xe2x88x9210 to 200xc2x0 C. (preferably 0 to 150xc2x0 C.) for 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
When the hydroxyl-protecting group is an alkenyloxycarbonyl group, it can be removed by treating with a base under similar conditions to those employed when the hydroxyl-protecting group is the above-described aliphatic acyl, aromatic acyl or alkoxycarbonyl group.
Incidentally, when the protecting group is an allyloxycarbonyl group, it can be removed more easily with less side reactions by using, in particular, palladium and triphenylphosphine or bis(methyldiphenylphosphine) (1,5-cyclooctadien)iridium (I).hexafluorophosphate.
By the above-described reaction wherein Compound (VII) and an acid are brought into contact or the catalytic reduction of Compound (VII), the amino-protecting group and/or hydroxyl-protecting group happen to be removed at the same time.
The amino-protecting group and/or hydroxyl-protecting group can be removed successively in the desired order.
After the completion of the reaction, the resulting compound (Ia) of the present invention can be obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter by filtration; adding to the filtrate an organic solvent which is not miscible with water such as ethyl acetate; separating the organic layer containing the desired compound and washing with water or the like; drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation or chromatography. 
In the above reaction scheme, R1, R1a, R2, R2a, A and B have the same meanings as described above, X represents the above-described halogen atom and Y represents an oxygen or sulfur atom.
Method B is a process for the preparation of Compound (Ib) which is Compound (I) wherein R3 is the formula (IV-2) or (IV-3) or Compound (Ic) which is Compound (I) wherein R3 is the formula (IV-1).
Step B1 is a step for preparing a compound of formula (IX) by reacting Compound (V) with a base in the presence or absence (preferably, in the presence) of an inert solvent and then reacting the resulting compound with a compound of formula (VIII).
Examples of the base to be used for the above reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), of which the alkali metal hydrides (particularly, the sodium hydride) are preferred.
There is no particular limitation on the nature of the inert solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the amides (particularly, dimethylformamide) are preferred.
The temperature upon reaction of Compound (V) with the base depends on the natures of the raw materials, base and solvent, and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0 to 120xc2x0 C.).
The time upon reaction of Compound (V) with the base depends on the natures of the raw materials, base and solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 24 hours (preferably from 1 hour to 10 hours).
The temperature upon reaction of Compound (V) with Compound (VIII) usually ranges from xe2x88x9220 to 200xc2x0 C. (preferably from 0 to 150xc2x0 C.).
The time upon reaction of Compound (V) with Compound (VIII) usually ranges from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).
After the completion of the reaction, the resulting compound (IX) of the present reaction can be obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter by filtration, adding to the filtrate an organic solvent which is not miscible with water such as ethyl acetate and separating the organic layer containing the desired compound; washing with water or the like; drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The product so obtained can be isolated and purified, if necessary, by any suitable combination of conventional methods for example, recrystallization, reprecipitation or chromatography.
Step B2 is a step for preparing a compound of formula (XI) and it is carried out by reacting Compound (IX) with a compound of formula (X) in an inert solvent in the presence or absence (preferably in the presence) of a catalyst such as sodium acetate, piperidinium acetate or piperidinium benzoate.
There is no particular limitation on the nature of the inert solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the amides (particularly, dimethylformamide) are preferred.
The reaction temperature depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from 0 to 200xc2x0 C. (preferably from 10xc2x0 C. to 150xc2x0 C.).
The reaction time depends on the natures of the raw materials, catalyst, solvent, the reaction temperature and the like, however, it usually ranges from 1 hour to 50 hours (preferably from 2 hours to 24 hours).
After the completion of the reaction, the resulting compound (XI) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography.
Step B3 is a step for preparing a compound of formula (Ib) by subjecting Compound (XI) to catalytic reduction in an inert solvent and then removing the amino-protecting group and/or hydroxyl-protecting group in R1a and R2a if necessary. The catalytic reduction and the removal, if desired, of the amino- and/or hydroxyl-protecting group are carried out in similar manners to those described in Step A2 of Method A.
Alternatively, this step can be carried out by reacting Compound (XI) with a metal hydride and then removing the amino- and/or hydroxyl-protecting group in R1a and R2a if necessary. The reaction between Compound (XI) and the metal hydride can be conducted in a similar method to that disclosed in WO93/1309A.
Step B4 is a step for preparing a compound of formula (Ic) by removing the amino- and/or hydroxyl-protecting group in R1a and R2l of Compound (XIa) which is Compound (XI) having a sulfur atom as Y. This step is carried out in a similar manner to that described in Step A2 of Method A for the removal of the amino- and/or hydroxyl-protecting group. 
In the above reaction scheme, R1, R1a, R2, R2a, A and B have the same meanings as described above.
Method C is a process for preparing Compound (Id) which is Compound (I) wherein R3 is of the formula (IV-4) or Compound (Ie) which is Compound (I) wherein R3 is of the formula (IV-5).
Step C1 is a step for preparing the compound of formula (XII) by reacting Compound (IX) with hydroxylamine (hydrochloride) in an inert solvent and then contacting the reaction mixture with a reducing agent.
There is no particular limitation on the nature of the inert solvent to be used upon reaction of Compound (IX) with hydroxylamine (hydrochloride) provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; and mixtures of the above-exemplified solvents, of which the mixed solvents with an alcohol (particularly, methanol or ethanol) are preferred.
The temperature upon reaction of Compound (IX) with hydroxylamine (hydrochloride) depends on the natures of the raw materials, catalyst, solvent and the like, however, it usually ranges from xe2x88x9220 to 200xc2x0 C. (preferably from 10 to 120xc2x0 C.).
The time upon reaction of Compound (IX) with hydroxylamine (hydrochloride) depends on the natures of the raw materials, catalysts, solvent, the reaction temperature and the like, however, it usually ranges from 1 hour to 50 hours (preferably from 2 hours to 24 hours).
Examples of the reducing agent to be used in the latter stage of the reaction include alkali metal borohydrides such as sodium borohydride, lithium borohydride and sodium cyanoborohydride and aluminum hydrides such as diisobutylaluminum hydride, lithium aluminum hydride and lithium triethoxide aluminum hydride, of which the alkali metal borohydrides (particularly, sodium borohydride) are preferred.
There is no particular limitation on the solvent to be used upon the contact with the reducing agent in the latter stage of the reaction, provided that it has no adverse effect on the present reaction. Solvents similar to those used upon the reaction between Compound (IX) and hydroxylamine (hydrochloride) are preferably employed.
The reaction temperature upon contact with the reducing agent in the latter stage of the reaction depends on the natures of the raw material, reducing agent, solvent, and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0xc2x0 C. to 1 20xc2x0 C.).
The reaction time upon contact with the reducing agent in the latter stage of the reaction depends on the natures of the raw material, reducing agent, solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 24 hours (preferably from 1 hour to 12 hours).
After the completion of the reaction, the resulting compound (XII) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter, from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography.
Step C2 is a step for preparing a compound of formula (XIII) by reacting Compound (XII) with trimethylsilyl isocyanate in an inert solvent.
There is no particular limitation on the nature of the solvent to be used for the above reaction, provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the aromatic hydrocarbons, ethers and amides (particularly, diethyl ether, tetrahydrofuran and dimethylformamide) are preferred.
The reaction temperature depends on the natures of the raw materials, solvent and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0xc2x0 C. to 120xc2x0 C.).
The reaction time depends on the natures of the raw materials, solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 48 hours (preferably from 1 hour to 24 hours).
After the completion of the reaction, the resulting compound (XIII) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography.
Step C3 is a step for preparing a compound of formula (Id) by reacting Compound (XIII) with a carbonylating agent in an inert solvent and then removing the amino- and/or hydroxyl-protecting group in R1a and R2a if necessary.
There is no particular limitation on the nature of the carbonylating agent to be used in the above reaction provided that it is ordinarily employed for carbonylation. Examples include phosgene, diphosgene, triphosgene and 1,1xe2x80x2-carbonyldiimidazole.
There is no particular limitation on the nature of the solvent to be used upon the reaction of Compound (XIII) with the carbonylating agent, provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the aromatic hydrocarbons, halogenated hydrocarbons, ethers and amides (particularly tetrahydrofuran, dioxane and dimethylformamide) are preferred.
The temperature upon reaction of Compound (XIII) with the carbonylating agent depends on the natures of the raw materials, solvent and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0 to 120xc2x0 C.).
The time upon reaction of Compound (XIII) with the carbonylating agent depends on the natures of the raw materials, solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 50 hours (preferably from 1 hour to 24 hours).
The removal of the amino- and/or hydroxyl-protecting group in R1a and R2a is carried out if necessary in a similar manner to that described in Step A2 for the removal of the amino- and/or hydroxyl-protecting group.
After the completion of the reaction, the resulting compound (Id) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The product so obtained can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography.
Step C4 is a step for preparing a compound of formula (Ie) by removing the amino- and/or hydroxyl-protecting group in R1 and R2 of Compound (XIII) in an inert solvent. This step is conducted in a similar manner to that described in Step A2 of Method A for the removal of the amino- and/or hydroxyl-protecting groups.
Step C5 is another step for preparing a compound of formula (Id) by reacting Compound (XII) with N-(chlorocarbonyl)isocyanate in the presence or absence (preferably in the presence) of an inert solvent and then removing the amino- and/or hydroxyl-protecting group in R1a and R2a if desired.
There is no particular limitation on the nature of the solvent to be used upon the reaction of Compound (XII) with N-(chlorocarbonyl)isocyanate, provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the aromatic hydrocarbons, halogenated hydrocarbons, ethers and amides (particularly, tetrahydrofuran, dioxane and dimethylformamide) are preferred.
The reaction temperature depends on the natures of the raw materials, solvent and the like, however, it usually ranges from xe2x88x9250 to 100xc2x0 C. (preferably from xe2x88x9220 to 50xc2x0 C.).
The reaction time depends on the natures of the raw materials, solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 50 hours (preferably from 1 hour to 24 hours).
The removal of the amino- and/or hydroxyl-protecting group in R1a and R2a is carried out, if desired, in a similar manner to that described in Step A2 of Method A for the removal of the amino- and/or hydroxyl-protecting group.
After the completion of the reaction, the resulting compound (Id) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The product so obtained can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R2, R2a, R4, R5, R6, A, B, D, E and Y have the same meanings as described above; R4a represents a similar group to that in the definition of the group of R4 except that the amino and/or hydroxyl group included in the definition of R4 means an amino and/or hydroxyl group which may be protected by an amino- and/or hydroxyl-protecting group; R5a represents a similar group to that in the definition of the group of R5 except that the amino and/or hydroxyl group included in the definition of R5 means an amino and/or hydroxyl group which may be protected by an amino- and/or hydroxyl-protecting group; R7 represents a formyl, carboxy or C2-7 alkoxycarbonyl group and Boc means a t-butoxycarbonyl group.
Method D is a process for preparing Compound (Ifa) which is Compound (I) wherein R1 is a group of formula (II) and R3 is a group of formula (IV-2) or (IV-3) or Compound (Ifb) which is Compound (I) wherein R1 is a group of formula (III) and R3 is a group of formula (IV-2) or (IV-3).
Step D1 is a step for preparing the compound of formula (Ifa) and it is effected by reacting a compound of formula (XIV) with a compound of formula (XVa) and then removing the amino- and/or hydroxyl-protecting group in R2a, R4a and R5a if necessary.
When R7 in Compound (XIV) represents a formyl group, Compound (XIV) is reacted with Compound (XVa) in an inert solvent and then the t-butoxycarbonyl group which is an amino-protecting group is removed from the reaction mixture by using an acid for effecting ring closure, followed by reaction with an oxidizing agent.
Alternatively, this step can be carried out by reacting Compound (XIV) with Compound (XVa), isolating and purifying the intermediate obtained by removing the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid from the reaction mixture to effect ring closure, and then bringing an oxidizing agent into contact with the resulting intermediate.
There is no particular limitation on the nature of the solvent to be used upon the reaction of Compound (XIV) with Compound (XVa), provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethylsulfoxide; sulfolane; and mixtures of the above-exemplified solvents, of which the ethers (particularly, tetrahydrofuran) are preferred.
The temperature upon the reaction of Compound (XIV) with Compound (XVa) depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from 0 to 200xc2x0 C. (preferably from 10 to 120xc2x0 C.).
The reaction time upon the reaction of Compound (XIV) with Compound (XVa) depends on the natures of the raw materials, base, solvent, the reaction temperature and the like, however, it usually ranges from one hour to 50 hours (preferably from 5 hours to 24 hours).
The removal of the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid is carried out in a similar manner to that described in Step A2 for the removal of the alkoxycarboxyl group which is an amino-protecting group.
There is no particular limitation on the nature of the oxidizing agent to be used for the above reaction provided that it is ordinarily used in oxidizing reactions. Examples include inorganic metal oxidizing agents, for example, manganese oxides such as potassium permanganate and manganese dioxide; ruthenium oxides such as ruthenium tetroxide; selenium compounds such as selenium dioxide; iron compounds such as ferric chloride; osmium compounds such as osmium tetroxide, potassium osmate dihydrate (K2OsO4.2H2O); silver compounds such as silver oxide; mercury compounds such as mercury acetate; lead oxide compounds such as lead oxide and lead tetraacetate; chromic acid compounds such as potassium chromate, chromic acid-sulfuric acid complex and chromic acid-pyridine complex; and cerium compounds such as cerium ammonium nitrate (CAN); inorganic oxidizing agents, for example, such as halogen molecules such as chlorine molecules, bromine molecules and iodine molecules; periodic acid compounds such as sodium periodate; ozone; hydrogen peroxide; nitrous acid compounds such as nitrous acid; chlorous acid compounds such as potassium chlorite and sodium chlorite; and persulfuric acid compounds such as potassium persulfate and sodium persulfate; and organic oxidizing agents, for example, reagents used for DMSO oxidation (complexes between dimethylsulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentaoxide or a complex between pyridine and sulfuric anhydride); combination of a peroxide such as t-butylhydroperoxide and a vanadium or molybdenum complex; stable cations such as triphenylmethyl cations; combination of a succinic imide such as N-bromosuccinic imide and an alkali; oxiranes such as dimethyldioxirane; hypochlorous acid compounds such as t-butyl hypochlorite; azodicarboxylic acid compounds such as azodicarboxylate ester; peracids such as m-chloroperbenzoic acid and perphthalic acid; disulfides such as dimethyl disulfide, diphenyl disulfide and dipyridyl disulfide and triphenyl phosphine; nitrous acid esters such as methyl nitrite; tetrahalogenated carbons such as methane tetrabromide; and quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), of which halogen molecules (particularly, iodine molecules) are preferred.
There is no particular limitation on the nature of the solvent to be employed upon contacting with the oxidizing agent, provided that it has no adverse effect on the present reaction. Solvents used upon the reaction of Compound (XIV) with Compound (XVa) are preferably employed.
The reaction temperature and reaction time upon contacting with the oxidizing agent are similar to those employed upon the reaction of Compound (XIV) with Compound (XVa).
When R7 in Compound (XIV) represents a carboxyl group, the compound of formula (XIV) or reactive derivative thereof (an acid halide, active ester or mixed acid anhydride) is reacted with a compound of formula (XVa) or an acid addition salt thereof (e.g. the salt of a mineral acid such as a hydrochloride, nitrate or sulfate) and then the t-butoxycarbonyl group which is an amino-protecting group is removed using an acid, followed by ring closure.
In this step, alternatively, it is possible to isolate and purify the amide compound which is to be an intermediate, remove the t-butoxycarbonyl group, which is an amino-protecting group, from the resulting amide compound in a similar manner to that described in the above step, and then effect ring closure.
The acid halide method is carried out by reacting Compound (XIV) with a halogenating agent (e.g. thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl dichloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride) to prepare its acid halide and then reacting the resulting acid halide with Compound (XVa) or an acid addition salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base.
Examples of the base to be used for the above reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), of which the organic amines (particularly, triethylamine) are preferred.
There is no particular limitation on the nature of the solvent to be used in the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; hydrogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane, of which the halogenated hydrocarbons, ethers and amides are preferred (dichloromethane, chloroform, tetrahydrofuran and dimethylformamide are particularly preferred).
The reaction temperature depends on the natures of the raw materials, reagents and the like, however, it usually ranges from xe2x88x9220 to 150xc2x0 C. in each of the reaction of the halogenating agent with Compound (XIV) and the reaction of the acid halide with Compound (XVa) or an acid addition salt thereof. Preferably, the reaction of the halogenating agent and Compound (XIV) is carried out at a temperature of from xe2x88x9210 to 100xc2x0 C., while that of the acid halide with Compound (XVa) or an acid addition salt thereof is carried out at a temperature of from xe2x88x9220 to 100xc2x0 C.
The reaction time depends on the natures of the raw materials, reagents, the reaction temperature and the like, however, the reaction time ranges from 30 minutes to 80 hours (preferably from 1 hour to 48 hours) in each of the reaction of the halogenating agent with Compound (XIV) and that of the acid halide with Compound (XVa) or an acid addition salt thereof.
The active ester method is performed by reacting Compound (XIV) with an active esterifying agent in an inert solvent to prepare its active ester and then reacting the ester with Compound (XVa) or an acid addition salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base.
Examples of the active esterifying agent to be used in the above reaction include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; and triphenylphosphine.
There is no particular limitation on the nature of the solvent to be used for the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; and sulfolane, of which the ethers and amides (particularly, dioxane, tetrahydrofuran and dimethylformamide) are preferred.
The bases to be used in the above reaction are similar to those used in the above-described acid halide method.
The reaction temperature depends on the natures of the raw material and reagents and the like, however, the reaction of forming an active ester is usually carried out at a temperature of from xe2x88x9270 to 150xc2x0 C. (preferably from xe2x88x9210 to 100xc2x0 C.), while the subsequent reaction between the active ester and Compound (XVa) or an acid addition salt thereof is carried out at a temperature of from xe2x88x9220 to 100xc2x0 C. (preferably from 0 to 50xc2x0 C.).
The reaction time depends on the natures of the raw material, reagents, the reaction temperature and the like, however, it usually ranges from 30 minutes to 80 hours (preferably from 1 hour to 48 hours) in each of the reaction to prepare an active ester and the reaction of an active ester with Compound (XVa) or an acid addition salt thereof.
The mixed acid anhydride method is carried out by reacting Compound (XIV) and a mixed-acid-anhydride forming agent in an inert solvent in the presence or absence (preferably in the presence) of a base to prepare the corresponding mixed acid anhydride and then reacting the resulting mixed acid anhydride and Compound (XVa) or an acid addition salt thereof in an inert solvent.
Examples of the base to be used for the above reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium-t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropyl ethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), of which the organic amines (particularly, triethylamine) are preferred.
Examples of the mixed-acid-anhydride forming agent to be used in the above reaction include C1-4 alkyl halocarbonates such as ethyl chlorocarbonate and isobutyl chlorocarbonate; (C1-5 alkanoyl) halides such as pivaloyl chloride; and di(C1-4 alkyl) or di(C6-4 aryl) cyanophosphates such as diethyl cyanophosphonate and diphenyl cyanophosphonate, of which the di(C1-4 alkyl) or di(C6-14 aryl) cyanophosphates (particularly, diethyl cyanophosphonate) are preferred.
There is no particular limitation on the nature of the solvent to be used upon the preparation of the mixed acid anhydride provided that it has no adverse effect on the reaction and can dissolve therein the starting substance to some extent. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane, of which the ethers and amides (particularly, tetrahydrofuran and dimethylformamide) are preferred.
The temperature of reaction for preparing the mixed acid anhydride depends on the natures of the raw materials, reagents and the like, however, it usually ranges from xe2x88x9250 to 100xc2x0 C. (preferably from 0 to 60xc2x0 C.).
The time of reaction for preparing the mixed acid anhydride depends on the natures of the raw materials, reagents, reaction temperature and the like, however, it usually ranges from 30 minutes to 72 hours (preferably from 1 hour to 24 hours).
The mixed acid anhydride is reacted with Compound (XVa) or an acid addition salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base, and the base and inert solvent to be used for this reaction are similar to those employed in the reaction for the preparation of the above-described mixed acid anhydride.
The temperature of reaction of the mixed acid anhydride with Compound (XVa) or an acid addition salt thereof depends on the natures of the raw materials, reagents and the like, however, it usually ranges from xe2x88x9230 to 100xc2x0 C. (preferably from 0 to 80xc2x0 C.).
The time of reaction of the mixed acid anhydride with Compound (XVa) or an acid addition salt thereof depends on the natures of the raw materials, reagents, reaction temperature and the like, however, it usually ranges from 5 minutes to 24 hours (preferably from 30 minutes to 16 hours).
When a di(C1-4 alkyl)cyanophosphoric acid or di(C6-4 aryl)cyanophosphoric acid is employed in this reaction, Compound (XIV) can be reacted with Compound (XVa) directly in the presence of a base.
The removal of the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid is carried out in a similar manner to that described in step A2 of Method A for the removal of the protecting group from the alkoxycarbonyl-protected amino group by using an acid.
The ring-closure subsequent to the removal of the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid can be carried out in a similar manner to that described in step A2 of Method A for the removal of the protecting group from the alkoxycarboxy-protected amino group by using an acid.
When Compound (XIV) contains a C2-7 alkoxycarbonyl group as R7, Compound (XIV) is reacted with Compound (XVa) in the presence or absence (preferably in the absence) of an inert solvent and in the presence or absence of a base, the t-butoxycarbonyl group which is an amino-protecting group is removed using an acid, followed by ring closure.
In this step, alternatively, it is possible to isolate and purify the amide compound which is to be the intermediate, remove the t-butoxycarbonyl group, which is an amino-protecting group, from the resulting amide compound in a similar manner to described in the above reaction, and then effect ring closure.
Examples of the base to be used for the above reaction of Compound (XIV) with Compound (XVa) include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; and organic amines such as triethylamine, tributylamine, diisopropyl ethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), of which the organic amines (particularly, triethylamine) are preferred.
There is no particular limitation on the nature of the solvent to be used upon the reaction of Compound (XIV) with Compound (XVa) provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and mixtures of the above-exemplified solvents, of which the ethers and amides (particularly, tetrahydrofuran, dioxane and dimethylformamide) are preferred.
The reaction temperature depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from 0 to 200xc2x0 C. (preferably, from 50 to 150xc2x0 C.).
The reaction time depends on the natures of the raw materials, base, solvent, the reaction temperature and the like, however, it usually ranges from 1 hour to 50 hours (preferably from 5 hours to 24 hours).
The ring-closure subsequent to the removal of the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid can be carried out in a similar manner to that described in step A2 of Method A for the removal of the protecting group from the alkoxycarboxy-protected amino group by using an acid.
The removal, if necessary, of the amino- and/or hydroxyl-protecting group in R2a, R4a and R5a is carried out in a similar manner to that described in Step A2 of Method A for the removal the amino- and/or hydroxyl-protecting group.
After the completion of the reaction, the resulting compound (Ifa) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water such as ethyl acetate to the residue; separating the organic layer containing the target compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting compound can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chomatography.
Step D2 is a step for preparing the compound of formula (Ifb) and it is effected in a similar manner to that described in step D1 of Method D, more specifically, by reacting the compound of the formula (XIV) with the compound of the formula (XVb) and then removing the amino- and/or hydroxyl-protecting group in R2a, R4a and R5a if necessary. This step is carried out in a similar manner to that described in Step D1.
If R4 of Compound (Ia), (Ib), (Ic), (Id), (Ie), (Ifa) and (Ifb) obtained by the above-described Method A, Method B, Method C and Method D is a phenyl or pyridyl group substituted with an amino group, it is possible to carry out alkylation, arylation, aralkylation or acylation of the amino group if necessary. Such a reaction is known or can be effected in a known method or method analogous thereto [The Chemistry of the Amino Group, chapter 6, 1968, John Wiley and Sons, The Chemistry of the Amino Group, chapter 2, 1970, John Wiley and Sons, etc.]
The raw materials (V), (VI), (VIII), (X), (XIV), (XVa) and (XVb) are each known or are prepared easily by a known method or a method analogous thereto.
The raw materials (V), (XIV), (XVa) and (XVb) can also be prepared, for example, by the following methods. 
In the above reaction scheme, R4a, R5a, R6, R7, A, B, D, E and Boc have the same meanings as described above.
Method E is a process for preparing Compounds (Va) and (Vb).
Step E1 is a step for preparing Compound (Va) by reacting a compound of formula (XVI) with Compound (XVa) and then removing the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid, followed by ring closure. This step is conducted in a similar manner to that described in Step D1 of Method D wherein Compound (XIV) is reacted with Compound (XVa) and the t-butoxycarbonyl group, which is an amino-protecting group, is removed by using an acid, followed by ring closure.
In particular, when, in Compound (XVa), E represents a nitrogen atom, the ring closure is preferably carried out using Compound (XVI) in a large excess amount in the absence of a solvent.
Step E2 is a step for preparing Compound (Vb) by reacting the compound of the formula (XVI) with Compound (XVb) and then removing the t-butoxycarbonyl group, which is an amino-protecting group, by using an acid. This step is carried out in a similar manner to that described in Step D1 of Method D, wherein Compound (IXV) having a carboxyl group as R7 is reacted with Compound (XVa) and then the t-butoxycarbonyl group, which is an amino-protecting group, is removed by using an acid.
The ring closure is also conducted in a similar manner to that described in Step D1 of Method D. When, in Compound (XVa), E represents a nitrogen atom, however, the ring closure is preferably carried out using a large excess amount of Compound (XVI) in the absence of a solvent.
After the completion of the reaction, the resulting compound (Va) or (Vb) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R2a, R7, R8, A, B, X and Y have the same meanings as described above and R7a represents a similar group to that in the definition of R7 except that the formyl or carboxyl group included in the definition of R7 means a formyl or carboxyl group which may be protected by a protecting group.
In the above description, there is no particular limitation on the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9cformyl group which may be protected by a protecting groupxe2x80x9d provided that it is a formyl-protecting group used in the field of organic synthetic chemistry. Examples include a methyl group substituted with the above-exemplified C1-6 alkoxy groups, such as dimethoxymethyl, diethoxymethyl, dipropoxymethyl and dibutoxymethyl, and 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1,3-dithian-2-yl and 1,3-dithiolan-2-yl groups, of which dimethoxymethyl, diethoxymethyl, 1,3-dioxolan-2-yl and 1,3-dithian-2-yl groups are preferred.
In the above description, there is no particular limitation on the xe2x80x9cprotecting groupxe2x80x9d of the xe2x80x9ccarboxyl group which may be protected by a protecting groupxe2x80x9d provided that it is a carboxyl-protecting group used in the field of organic synthetic chemistry. Examples include C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl and t-butyl; and C1-6 alkyl groups substituted with 1 to 3 C6-10 aryl groups which may be substituted with a C1-6 alkyl group, C1-6 alkoxy group, nitro group, halogen atom or cyano group, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-fluorobenzyl and 4-cyanobenzyl groups, of which the C1-6 alkyl groups and benzyl group are preferred.
Method F is a process for preparing Compound (XIV).
Step F1 is a step for preparing Compound (XIV) by reacting the compound of formula (XVII) with a compound of formula (XVIII) in an inert solvent in the presence of a base and then removing the protecting group if the formyl or carboxyl group of R7a is a protected formyl or carboxyl group.
The base employed upon reacting the compound of formula (XVII) with the compound of the formula (XVIII) is similar to that used in the above-described Step B1 of Method B and is preferably an alkali metal hydride (particularly, sodium hydride).
The solvent employed upon reacting the compound of formula (XVII) with the compound of formula (XVIII) is similar to that used in the above-described Step B1 of Method B and is preferably an amide or a mixed solvent of an amide and another solvent (particularly, dimethylformamide).
The reaction temperature upon reacting the compound of formula (XVII) with the compound of formula (XVIII) depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0 to 120xc2x0 C.).
The reaction time upon reacting the compound of formula (XVII) with the compound of formula (XVIII) depends on the natures of the raw materials, base, solvent, the reaction temperature and the like, however, it usually ranges from 30 minutes to 24 hours (preferably from 1 hour to 10 hours).
The removal, if desired, of the protecting group of the formyl group or carboxyl group depends on its nature, however, it is generally carried out by a method known in the field of organic synthetic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley and Sons or J. F. W. McOmie, (Protective Groups in Organic Chemistry), Plenum Press.
Compound (XIV) wherein R7 is a carboxyl group or Compound (XVIII) wherein R7a is a carboxyl group can be easily prepared by a known method from a compound wherein R7 or R7a represents a formyl or protected formyl group.
After the completion of the reaction, the resulting compound (XIV) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R2a, R7, R7a, A, B, X and Y have the same meanings as described above and R9 represents a carboxyl-protecting group (which has the same meaning as described above).
Method G is also a preparation process of Compound (XIV), and is different from Method F.
Step G1 is a step for preparing a compound of formula (XXI) by reacting a compound of formula (XIX) with a compound of formula (XX) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described in Step F1 of Method F.
Step G2 is a step for preparing a compound of formula (XXII) by reduction of Compound (XXI). This reaction is carried out by catalytic reduction or the zinc-acetic acid method, tin-alcohol method or tin-hydrochloric acid method which is usually employed for the reduction of a nitro group.
Step G3 is a step for preparing a compound of formula (XXIII) and it is achieved by subjecting Compound (XXII) to a Meerwein arylation in a similar method to that described in Japanese Patent Application Kokai No. Sho 55-22657 (U.S. Pat. No. 4,258,193) or S. Oae et al., xe2x80x9cBull. Chem. Soc. Jpn., 53, 1065(1980)xe2x80x9d.
Step G4 is a step for preparing Compound (XIV) by reacting Compound (XXIII) with a compound of formula (XXIV) and then subjecting the reaction mixture to hydrolysis, and if desired, removing the formyl- or carboxyl-protecting group as defined in the group of R7a.
The reaction of Compound (XXIII) with Compound (XXIV) and hydrolysis subsequent thereto are carried out in a similar method to that described in Japanese Patent Application Kokai No. Sho 55-22657 (U.S. Pat. No. 4,258,193).
The removal of the formyl- or carboxyl-protecting group which is defined in the group of R7a is carried out in a similar method to that described in the removal of the formyl- or carboxyl-protecting group in Method F.
After the completion of the reaction, the resulting compound (XIV) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The compound so obtained can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R4a, R5a, R6, D, E, X and Boc have the same meanings as described above.
Method H is a process for preparing Compounds (XVa) and (XVb).
Step H1 is a step for preparing a compound of formula (XXVIIa) by reacting a compound of formula (XXV) with a compound of formula (XXVIa) in the presence of a base. This step is carried out in a similar manner to that described in Step F1 of Method F.
Step H2 is a step for preparing Compound (XVa) by reduction of Compound (XXVIIa). This step is carried out in a similar manner to that described in Step G2 of Method G.
Step H3 is a step for preparing Compound (XXVIIb) by reacting a compound of formula (XXV) with a compound of formula (XXVIb) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described in Step F1 of Method F.
Step H4 is a step for preparing Compound (XVb) by reduction of Compound (XXVIIb). This step is carried out in a similar manner to that described in Step G2.
After the completion of the reaction, the resulting compounds (XVa) and (XVb) of the present reaction are obtained from the reaction mixture by a known method. For example, each of them can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate to the residue; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting compound can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R5a, R6, E, X and Boc have the same meanings as described above.
Method I is a process for preparing Compounds (XXVIa) and (XXVIb).
Step I1 is a step for preparing a compound of formula (XXIXa) by protecting the amino group of a compound of formula (XXVIIa) with a t-butoxycarbonyl group in a similar method to that ordinarily known in the field of organic synthetic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis), John Wiley and Sons or J. F. W. Mcomie, (Protective Groups in Organic Chemistry), Plenum Press.
Step I2 is a step for preparing Compound (XXVIa) by reacting Compound (XXIXa) with a compound of formula (XXX) in an inert solvent in the presence of a base.
The base used in the above reaction is similar to that used in the above-described Step B1 of Method B and alkali metal hydrides (particularly sodium hydride) are preferred.
The solvent used in the above reaction is similar to that used in Step B1 of Method B and ethers and amides (particularly, tetrahydrofuran, dioxane and dimethylformamide) are preferred.
The reaction temperature depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from xe2x88x9250 to 200xc2x0 C. (preferably from 0 to 120xc2x0 C.).
The reaction time depends on the natures of the raw materials, base, solvent, the reaction temperature and the like, however, it usually ranges from 30 minutes to 24 hours (preferably from 1 hour to 10 hours).
Step I3 is a step for preparing a compound of formula (XXIXb) by protecting the amino group of the compound of the formula (XXVIIIb) with a t-butoxycarbonyl group. This step is carried out in a similar manner to that described in Step I1.
Step I4 is a step for preparing Compound (XXVIb) by reacting Compound (XXIXb) with a compound of formula (XXX) in an inert solvent in the presence of a base. This step is carried out in a similar manner to that described in the above-described Step I2 of Method I.
After the completion of the reaction, the resulting compound (XXVIa) or (XXVIb) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture if necessary; removing the insoluble matter from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound, washing with water or the like and drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by any suitable combination of conventional methods, for example, recrystallization, reprecipitation and chromatography. 
In the above reaction scheme, R5a, R6, D, E and Boc have the same meanings as described above, R10 represents a hydrogen atom or a triphenylmethyl group and the group of the following formula: 
represents a phenyl group which may be substituted with 1 to 4 substituents selected from Substituents xcex1 or a pyridyl group which may be substituted with 1 to 3 substituents selected from Substituents xcex1.
Method J is a process for preparing Compound (XVd) or (XVf) having as R4a a phenyl or pyridyl group substituted with a tetrazolyl group which may be protected, and is different from Method H.
Step J1 is a step for preparing Compound (XVd) by reacting Compound (XVc), which is Compound (XVa) having as R4 a cyano-substituted phenyl or pyridyl group, with an azide compound in an inert solvent and then, if desired, protecting the tetrazolyl group of the resulting compound.
There is no particular limitation on the nature of the inert solvent to be used upon the above reaction provided that it has no adverse effect on the present reaction. Examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoryl triamide; and sulfoxides such as dimethylsulfoxide, of which the aromatic hydrocarbons (particularly, toluene) are preferred.
Examples of the azide compound to be used in the above reaction include diarylphosphoryl azide derivatives such as diphenylphosphoryl azide; trialkylsilylazides such as trimethylsilylazide and triethylsilylazide; alkali metal salts of azide such as sodium azide and potassium azide; and trialkyltin azides such as tri-n-butyltin azide, of which the trialkyltin azides (particularly the tri-n-butyltin azide) are preferred.
In the above reaction, the azide compound may be used either singly or in combination with, for example, a trialkylsilyl triflate such as trimethylsilyl triflate or triethylsilyl triflate or a Lewis acid such as trifluoroborane etherate, aluminum chloride or zinc chloride.
Although the reaction temperature depends on the natures of the raw material, azide to be employed and solvent, and the like, it usually ranges from xe2x88x9210 to 200xc2x0 C. (preferably from 50 to 150xc2x0 C.).
The reaction time depends on the natures of the raw material, azide to be employed and solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 48 hours (preferably from 30 minutes to 30 hours).
The reaction to protect the tetrazolyl group is carried out if necessary by reacting the compound obtained by the above reaction with a halogenated triphenylmethane in an inert solvent in the presence of a base.
The base used in the above reaction is similar to that used in Step B1 of Method B and organic amines (particularly triethylamine) are preferred.
The solvent used in the above reaction is similar to that used upon reaction of Compound (XVc) with an azide compound and a mixture of an ether and an amide (particularly, a mixture of tetrahydrofuran and dimethylformamide) is preferred.
The reaction temperature depends on the natures of the raw materials, base, solvent and the like, however, it usually ranges from xe2x88x9210 to 150xc2x0 C. (preferably from 0 to 60xc2x0 C.).
The reaction time depends on the natures of the raw materials, base and solvent, the reaction temperature and the like, however, it usually ranges from 15 minutes to 48 hours (preferably from 30 minutes to 30 hours).
Step J2 is a step for preparing the compound of the formula (XVf) by reacting Compound (XVe), which is Compound (XVb) having as R4a a cyano-substituted phenyl or pyridyl group, with an azide compound and if necessary, protecting the tetrazolyl group of the resulting compound. This step is carried out in a similar manner to that described in Step J1 of Method J.
After the completion of the reaction, the resulting compound (XVd) or (XVf) of the present reaction is obtained from the reaction mixture by a known method. For example, it can be obtained by neutralizing the reaction mixture as desired; removing the insoluble matter, if any, from the reaction mixture by filtration and adding to the filtrate an organic solvent, which is not miscible with water, such as ethyl acetate; separating the organic layer containing the desired compound from the resulting mixture, washing the organic layer with water or the like and drying it over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like; and then distilling off the solvent. The resulting product can be isolated and purified, if necessary, by using in combination the methods ordinarily employed for the separation and purification of an organic compound such as recrystallization, reprecipitation, and chromatography using an appropriate eluant.
The raw materials (XVI), (XVII), (XVIII), (XIX), (XX), (XXIV), (XXV), (XXVIIIa), (XXVIIIb) and (XXX) are known or easily prepared by a known method or a method analogous thereto [e.g. Japanese Patent Application Kokai Hei 9-188669 (EP543662A) and the like].
(Advantages of the Invention)
The compound of formula (I) or a pharmacologically acceptable salt thereof according to the present invention has excellent insulin-resistance improving action, blood sugar lowering action, anti-inflammatory action, immunomodulatory action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, lipid peroxide production inhibitory action, PPAR activating action, anti-osteoporosis action, leukotriene antagonism, fat-cell-formation promoting action, cancer-cell proliferation inhibitory action and calcium antagonism and is therefore useful as a preventive agent and/or remedy for diabetes, hyperlipidemia, obesity, glucose tolerance insufficiency, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts or coronary disease and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g. brain injury induced by stroke and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (such as arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune diseases and pancreatitis), cancer, osteoporosis or cataracts.
In addition, the compound of formula (I) or a pharmacologically acceptable salt thereof according to the present invention is useful as a pharmaceutical composition (particularly, as a preventive agent and/or remedy for diabetes or diabetic complications) obtained by using it in combination with at least one of xcex1-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
[Industrial Applicability]
When the compound of formula (I) or a pharmacologically acceptable salt or prodrug thereof is used according to the present invention, it can be administered as it is or, if necessary, after being mixed with a pharmacologically acceptable excipient, diluent or the like, orally as tablets, capsules, granules, powders or syrups or parenterally as injections or suppositories.
The above pharmaceutical formulations can be prepared in a known manner by using additives. Examples of the additives include an excipient (e.g. organic excipients, for example, sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch and dextrin; and cellulose derivatives such as crystalline cellulose, gum arabic, dextran, and pullulan; and inorganic excipients, for example, silicate derivatives such as soft silicic anhydride, synthetic aluminum silicate, calcium silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium hydrogenphosphate; carbonate derivatives such as calcium carbonate; and sulfates such as calcium sulfate), a lubricant (e.g. stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; wax such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicic hydrate; and the above-exemplified starch derivatives), a binder (e.g. hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, Macrogol and compounds similar to those described in the above excipient), a disintegrator (e.g. cellulose derivatives such as low degree substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium and internally crosslinked carboxymethyl cellulose sodium, and chemically-modified starch-cellulose such as carboxymethyl starch, carboxymethyl starch sodium and crosslinked polyvinyl pyrrolidone), a stabilizer (e.g. a paraoxybenzoate such as methyl paraben and propyl paraben; an alcohol such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol and phenol derivatives such as cresol; thimerosal; dehydroacetic acid; and sorbic acid), a corrigent (e.g. an ordinarily-employed sweetener, acidifier or flavor), and diluent; all of the foregoing are included within the term xe2x80x9cpharmaceutical carrierxe2x80x9d.
The dose of a drug of the invention will vary depending upon the condition and age of the patient (i.e., a warm-blooded animal and particularly a human), administration method and the like. Orally, it is administered in an amount of 0.001 mg/kg of body weight (preferable 0.01 mg/kg weight) in a single dose as a lower limit and 500 mg/kg of body weight (preferably 50 mg/kg weight) in a single dose as an upper limit, while intravenously, it is administered in an amount of 0.005 mg/kg weight (preferably, 0.05 mg/kg weight) in a single dose as a lower limit and 50 mg/kg weight (preferably, 5 mg/kg weight) in a single dose as an upper limit. It is desirable to be administered in one to several portions per day depending upon the conditions of the patient.
The present invention will hereinafter be described more specifically by examples, Reference Examples and pharmacological test examples. It should, however, be borne in mind that the present invention is not limited to or by these examples.